Mediated Regulation Of Tumor Cell Apoptosis Biology Essay

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Programmed cell death/apoptosis is a genetically conserved phenomenon involved in many biological processes including reconstruction of multi-cellular organisms and elimination of old or damaged cells. It is regulated by the activation/deactivation of protein kinase C in response to exogenous and endogenous stimuli. PKC is activated under stress by a series of downstream signaling cascade, which ultimately induces HSF1 activation that results in over expression of HSPs. Overexpression of HSPs interfere in apoptotic pathway while their blocking results in apoptosis. Therefore, HSF1 could be a novel therapeutic target against variety of tumors. Several pharmacological inhibitors of PKC have been demonstrated to exertinhibitory effect on the activation of HSF1 and therefore induce apoptosis in tumor cells. However, studies regarding the role of pharmacological inhibitors in the regulation of apoptosis and possible anti-tumor therapeutic intervention is still unknown or in its infancy. Therefore, in this review, an attempt has been made to understand the precise implication of HSF1 in the regulation of apoptosis and the role of pharmacological inhibitors of PKC in the regulation of HSF1 activation and its involvement in p53 dependent or independent apoptotic pathways.

Key Words: Apoptosis, HSF1, Protein Kinase C, Apoptotic factors, Cancer therapeutics


Apoptosis is a type of programmed cell death in which a cell utilizes its own machinery to commit suicide under tightly controlled physiological conditions. It is an evolutionarily highly conserved and genetically programmed developmental process which determines cell fate and acts as defence mechanism(s) against pathogen infected cells and those which have accumulated undesirable mutations. It represents mutually exclusive cellular processes to distinct stimuli [1]. There are two distinct forms of cell death, apoptosis and necrosis, which are distinct from each other [2]. Apoptosis; where cellular content remains "well-packed" in the apoptotic bodies and inflammation does not occur, on the other hand necrosis; where the cell membrane loses its integrity and cellular contents are released outside the cells causing an inflammatory response (Figure 1).

Although there is a quite dissimilarity in the mechanism(s) of apoptosis and necrosis but both processes are related/linked to each other. Recent studies suggest that both apoptosis and necrosis exhibit altered expression of some common biochemical events described as the apo-necrosis [3]. There might be two factors that can change the ongoing apoptotic pathway into necrotic pathway; one is reduced availability of cleaved caspases and reduced intracellular ATP pool Therefore, the fate of cells depends on the nature of signal that determines whether it dies by apoptosis or necrosis during developmental stages or in physiological milieu [6, 7]. Apoptosis is emerging as key biological regulatory mechanism, induced by intracellular stimuli and environmental assault. Malfunction in apoptotic process might results in degenerative disorder, cancer and autoimmune disease. Therefore, organisms require physiological defense mechanism(s) against environmental stresses. These defense mechanism(s) are under the control of genetic machinery in order to prevent or induce cell death depending upon the strength of the stress. Physiological stressors, by a series of downstream signaling cascade, induce HSF1 nuclear translocation and its activation leading to over expression of HSPs which play a central role cytoprotection by preventing cell death under stresses [8, 9].

Molecular mechanism of apoptosis

The pathways of apoptosis are extremely complicated, where the energy dependent flow of molecular events takes place. There are two types of apoptotic pathways intrinsic and extrinsic (or death receptor-initiated) which have been characterized by the involvement of a number of apoptogenic proteins. However, there are several common proteins which involved in both extrinsic and intrinsic pathway of apoptosis Table 1 [10, 11].

Intrinsic apoptotic pathway involves a distinct mode of non-receptor mediated apoptotic stimuli which integrates downstream signals directly to targets within the cells and is mitochondrial-dependent events. These incidences might be responsible for initiating intrinsic apoptotic pathway by integratiing intracellular biochemical events that can act either in a positive or a negative fashion. Negative effects exert deprivation of essential growth factors, hormones and related cytokines which result into inhibition of death programs whereas their accumulation triggered apoptosis. In addition, heavy metals, heat shock, infection and diseases are factors that exert positive effect to death progrms (Figure 2). These events can cause changes in mitochondrial membrane potential, resulted in an opening of mitochondrial permeability transition (MPT) pore, loss of mitochondrial membrane potential and release of apoptogenic factors such as cyt-c into cytosol [12]. Moreover, in normal physiological conditions, caspases occur in an inactive form (i.e. procaspases) and once activated can trigger cleavage of other uncleaved caspases or pro-caspases, inducing activation of a protease cascade leading to amplification of apoptotic signaling events followed by cell death due to their proteolytic activity (Table 2). Released cyt-c, with Apaf-1 and procaspase-9 form a multi-protein complex structure known as "apoptosome" which consists of cyt-c, Apaf-1, pro-caspase 9 and ATP [13, 14]. Procaspase-9 activity is increased markedly within the apoptosome and undergoes subsequent autoprocessing between its large and small subunits at Asp315 residue to generate the processed p35/p12 form of the enzyme (C9-p35/p12)which in turns, recuites and activates the effector caspase-3. For the enzymatic activity of caspase-9, it must remain bound to the complex (apoptosome). Activation of effector caspases and subsquent mutation in p53 might be responsible for DNA fragmentation and a highly prominent chromatin condensation which are one of the characteristics of apoptosis [15]. Regulation of mitochondrial associated apoptotic events can occurs through the member of Bcl2 family proteins (Figure 3) [16]. Moreover, reports suggest that the tumor suppressor protein p53 has potential role in the regulation of member of Bcl2 family proteins. . However the mechanism(s) of action remain a question of some debate [17]. P53 itself regulated by the efflux and influx of Ca++ ions concentration in the intracellular pool. Reports indicate that there are about 25 genes identified which might influence mitochondrial membrane potential during apoptosis. These proteins indicate either pro-survival or pro-apoptotic characteristics therefore their ratio plays an important role in the execution of apoptosis. Pro-survival proteins with special domain organization include Bcl2, Bcl-xL, Bcl-w and BAG while pro-apoptotic proteins consist of Bax, cl-Xs, Bid Bad, Bim and Blk respectively. These proteins are essential since they have been identified whether a cell entrust to death or terminate the process. However, the mechanism(s) of action need a detail investigation but recent studies also suggest that these proteins promptly involved in the regulation of cyt-c release and thus apoptosis.

In contrast to intrinsic apoptotic pathway the extrinsic apoptotic pathway involves a receptor mediated interactions. Transmembrane receptor mediated amplification of death signals performed by a receptor gene super family includes members of the TNF receptor family consisting of similar cysteine-rich extracellular domains organization and a cytoplasmic domain with 80 amino acids long chain polypeptide known as the "Death Domain" (DD) [18,19]. Death domain plays an important role in signal amplification leading to initiation of apoptotic events in the cells.. There are several examples of ligands receptors interation but presently the most popular legends and corresponding death receptors include FasL/FasR, TNF-α/TNFR1, Apo3L/DR3, Apo2L/DR4-5 [20-24]. Although, sequence of biochemical events that execute extrinsic apoptotic pathway characterized by the FasL/FasR and TNF-α/TNFR1 models. Fas-associated death domain (FADD) has C-terminal domain that form homophilic association with DD on cytoplasmic tail of ligand receptor (Chinnaiyan et al. 1905), while N-terminal of FADD consists of a second death fold motif, a DED which help in binding of caspases monomer to N-terminal DED domains in another homophilic interaction, resulting in a localized interaction of caspases-8. At this juncture, a death-inducing signalling complex (DISC) is formed, resulting in self-cleavage of inactivated caspase-8 [25]. Activated caspase-8 induces apoptosis either by directly activating caspase-3 or through truncated Bid protein.

Comparing two classical apoptotic pathways (intrinsic and extrinsic), receptor mediated apoptotic pathway associated with extrinsic apoptotic pathway seems to be more recently evolved form of cell death pathway in higher organisms. Death receptor involved in apoptotic pathway of immune system includes perforin/granzyme-A or B (released by cytotoxic T lymphocytes and NK cells). Granzyme A-induces caspase-independent apoptosis throughthrough single strand break of DNA [26]. Protein Kinase C is a family of serine/threnine kinase known to play an essential role in apoptosis. Activation of PKC isoforms induces changes in their sub-cellular localization, triggered by phospholipid diacylglycerol (DAG) and Ca++ ions [27]. Activated PKC integrates downstream signalling for other kinase phosphorylation [28, 29]. However, other forms of PKC can be activated independently in a redundant manner through phospholipase C (PLC) and phosphatidylinositol 3-kinase (PI3K) pathway [30]. The PKCs are involved in the phosphorylation of many signalling intermediate, which transduces apoptotic signals for its execution. Further, PKC activation has been considered to up-regulate the expression of anti-apoptotic factors such as Bcl2, Bcl-xl, Bcl-x, Bcl-w, BAG that prevent the execution of apoptotic events (Figure 4), while inhibition of PKC phosphorylation results in downregulation of anti-apoptotic factors and up-regulation of pro-apoptotic proteins such as Bax, Bak, Bid, Bad, Bim, Bik, Blk leading to greater ratio of pro-apoptotic proteins which results in apoptosis. Studies indicate that proteins associated with apoptosis might be located inside the mitochondria which work togather with pro-survival member of Bcl2 family proteins to induce , changes in mitochondrial membrane potential, release of cyt-c and subsequent activation of caspase-9. Activated caspase-9 further induces the cleavage of effector caspasess (Caspase-3) which further leads to apoptosis [31]. In addition, alteration in Ca++ concentration may alter p53 function, which ultimately triggerDNA fragmentation and therefore death of target cells. On the other hand, inactivated p53 (high Ca++ concentration results in p53 inactivation) results in HSF1 nuclear migration and its activation leading to over expression of HSPs (heat shock proteins) and subsequently, regulation of apoptosis and maintenance of cellular homeostasis..

Heat Shock Factors and Programmed Cell Death

Heat shock transcription factors (HSFs) regulate stress-inducible synthesis of HSPs during development, growth, adaptation, and stress [32-34]. In mammal, HSF gene family consists of HSF-1 to -4 [35-37]. HSF1 is a master transcription factor responsible for induced expression of HSPs [38, 39]. Under stress, PKC is activated, which in turn, activates HSF1 by phosphorylation of its serine/threonine residues. Activated HSF1 form homotrimer, an active form that binds to heat shock element (HSE) of the heat shock protein genes, which consist of multiple nGAAn modules that are arranged in alternating orientation. In addition, HSF2, HSF3 and HSF4 are do not play a major role in the synthesis of heat shock proteins under stress. Although non-specific heat shock proteins transcription is also regulated by these heats shock transactivators which required a HSE sequence on DNA. The HSEs are evolutionary conserved consensus sequence that form a complex with HSF1 and induces expression of HSPs under stress. Over expression of HSPs either directly or indirectly is considered to trigger phosphorylation of Bcl2 family proteins and their heterodimerization with BH3 domain of Bcl-xL. However, their downregulation may result in the induction of apoptosis. Further, studies indicate that expression of HSPs (hsp70) increases many fold after tissues or cells are exposed to a variety of stresses such as heavy metal, pro-inflammatory cytokines, heat shock, and malignancies [40,41]. Over expression of HSPs plays a vital role in maintaining cellular homeostasis against stresses, due to their chaperone function [42, 43]. In contrast, failure of their chaperone functions result in the induction of apoptosis while up regulation prevent apoptosis incurred due to stresses and thus promote tumor growth and progression [44]. The role of HSPs in altering cellular responses to an apoptotic stimulus is complex and, at present, incompletely understood. Concomitantly, decreased HSPs levels have been associated with a pro-apoptotic state (Figure 5) [45]. Therefore, HSPs play a more interesting role in controlling cellular homeostasis, serving more dynamic proteins, strong affinity extension of cytoskeleton, confiscating a surfeit of proteins, reorganized the concept of the "microtrabecular lattice" [46-48]. However, recent studies suggest that inhibition of total cytoplasmic hsp70/hsp90 either by specific inhibitors or with anti-hsp90 ribozyme and thereafter disruption of cytoplasmic hsp70-hsp90 complex organization induces cellular lysis under normal physiological conditions. This is in agreement that small HSPs (sHSP) family members are very well known for their preventive role Cyt c release and is therefore helpful for cell survival [51, 52]. Recent reports suggest that anti-hsp27 antibodies induce neuronal apoptosis by disrupting actin filaments [53]. The large HSP70 family members HSP105/HSP110 protect microtubules and displays an anti-apoptotic function [54]. These examples give a further emphasis on the role of HSPs in the stabilization of the cytoskeleton, cell architecture and thus in prevention of the apoptotic process.

Further, reports indicate that during stresses, increased expression of bcl-2 protein family has been observed, however the involvement of bcl-2 is likely to be small and prevent the nuclear condensation induced by heat shock. A second mechanism for the anti-apoptotic effect of HSPs might involve their interaction and subsequent inhibition of some of the proteins that drive programmed cell death. Hsp70 can interact with p53 [55-57] and able to modulate p53-dependent apoptosis of tumor cells. Hsp70 binding to the mutant p53 protein may function to stabilize p53 protein, abrogating the pro-apoptotic function of normal wild-type p53, thus contributing to tumorigenesis [58]. It suggests that the co-ordinate synthesis of all HSPs or other less abundant HSPs induced by stimuli, or possibly other unknown protective proteins may be involved in protecting cells against apoptosis. In contrast, induction of HSP synthesis has been reported to enhance apoptosis in certain cells. Reports employing hsp90-overexpressing transformed hematopoietic cells affirmed increased induction of apoptosis in response to TNF-α in combination with cycloheximide, but not to UV-B irradiation. Conversely, antisense transfected cells that express less hsp90 were relatively protected from apoptosis [59]. Liossis et al. found that hsp70 transfected Jurkat T cells were more prone to apoptotic cell death induced by cell surface receptors Fas/Apo-1/CD95 and TCR/CD3 [60, 61]. The apoptotic agonistic mechanisms of HSPs are largely unknown [60].

As noted previously, monoblastoid cell death are known to accomplish by a family of proteases known as caspases, and has recently been shown to be influenced by protein kinase C (PKC) through its ability to phosphorylate caspase-3 (Voss OH et al. 2005). In this context, particularly the PKC family of serine/threonine kinases has been implicated in the regulation of such processes. Activation of PKC by the endogenous substrate diacylgycerol/ Ca++ or pharmacological compounds like phorbol ester that binds to most PKC isoform leads to the induction of HSFs, in particular, HSF1[62]. Functional studies have demonstrated that inhibition of PKC in different cells/cell lines results in the induction of apoptosis in response to a variety of stimulus [63]. The cytoprotective effect of PKC results from phosphorylation, trimerization and binding of HSF1 to HSE and over expression of HSPs and apoptotic factors.

HSF1 and apoptotic factor expression

Recent reports suggest that HSF1 has profound role in cell viability,apoptosis, growth, development and differentiation. Yeast HSF1 expression has been found to be essential for cell viability during unstressed conditions [64-66], a property that has been previously related to regulation of constitutive HSP gene expression [67]. Interestingly, the Drosophila HSF1 protein is not essential for general growth or viability, but is required for larvae development, oogenesis, and survival at extreme stress conditions [68]. These initial studies are suggestive of involvement of HSF in the regulation of apoptosis. In vertebrates, multiple HSFs have been identified in chicks, plants, mice, and humans [69-72], which may exert redundant and/or complementary functions during growth, development, and physiological adaptation. In many cancer cell lines such as human pancreatobiliary tumors, the HSF1 has been found constitutively expressed where it plays a cytoprotective role and invariably helps in growth and progression of tumor cells. Inhibition of HSF1 expression by HSF1siRNA leads to time dependent death in both pancreatic and cholangiocarcinoma cell lines. Downregulation of HSF1 expression induces annexin V and TUNEL positivity and caspase 3 activation suggesting the activation of caspase-dependent apoptotic pathway in pancreatic cancer and cholangiocarcinoma cell lines [73].

HSF1 has been considered to affect the ratio of pro-survival to pro-apoptotic Bcl2 family proteins in colon cancer cells. Microarray studies on the expression of genes suggest a potential role of heat shock factor (HSF-regulated), BAG-1; against α-β-unsaturated aldehyde 4-hydroxynonenal (HNE) challenges [74]. Biochemical studies demonstrate that BG3 prevents cancer cell apoptosis by stabilizing Bcl-xL, Mcl-1, and Bcl-2. Earlier studies indicate that BAG-1exhibits an association with hsp70 and Bcl2 family proteins which can reverse the process of apoptosis. The proposed theory was also supported by the studies demonstrating the over expression of Bcl2 family proteins associated with over expression of HSPs through a number of heat shock inducing agentsHowever, the expression of BAG-1 has been detected significantly higher in Leukamia cell line in comparison to normal cell or tissue, suggesting its survival expectancy [76].

HSF1 has been demonstrated to act as a regulator of certain apoptosis-related genes, including interleukin (IL)-1β, c-fos and TNF-α gene [77-79], indicating its direct involvement in apoptotic process. Previous reports indicates that exposure of a mild heat shock rapidly sensitized Jurkat and HeLa cells to Fas-mediated apoptosis [80]. However, it has been reported that HeLa cells are relatively insensitive to Fas-mediated killing, but over-expression of a constitutively activated form of HSF1 (HSF1+) directly sensitize the cells to Fas-mediated killing [81]. In contrast, blocking of HSF1 function by specific inhibitor/non-specific inhibitor of serine/threonine kinase reduce the expression of HSPs which might lead to initiation of apoptotic cascade.

HSF1 in p53 regulation

Previous reports based on in vivo studies suggest that HSF1induces the development of spontaneous tumors in p53-/- mice. Mice lacking p53 results in rapid tumor progression that is mainly lymphoma while mice with p53-/-, Hsf1-/- developed lymphoma exceptionally but may develop in other types of cancer such as testicular carcinoma [Min JN et al. 2007]. Therefore, HSF1 deficiency remarkably reduces spontaneous tumor progression in mice with dominant-negative mutation of the p53 gene, while mice Hsf+/+ and Hsf1+/- with dominant-negative mutation of p53 develop a wide range of tumor types [Oren M, et al. 2010]. P53 regulates the cell cycle and transcription of growth-regulatory genes and ensures stability of genome by preventing mutation and thus designated as "guardian of the genome". Previous, studies indicate that p53 induces cell growth arrest or apoptosis under cellular stress, which indicates that it is an important protein that is directly/indirectly involved in the mechanism(s) of apoptosis. Wild type p53 is involved in the induction of apoptosis by interfering the homotrimerization and formation of HSE-HSF1 complex [84, 85], while mutant p53 can inhibit apoptosis by upregulating the expression of HSF1 resulting in enhanced synthesis of hsp70 [86-88]. The p53 is a transcription factor capable of binding DNA in a sequence-specific manner [89]. However, oncogenes that carry mutations itself are lost its ability to bind DNA and can induce alterations in p53 functions during tumorigenesis. Such ability of p53 has been considered significant in the regulation of apoptosis in some, although not all functional studies. Therefore, it can be considered that p53 directly upregulate the transcription of genes known to induce apoptosis. Moreover, recent reports on knock in mice suggest that mice were expressing transcriptionally dead p53. [95], suggesting transactivation of p53 is very essential for p53 to induce apoptosis of normal cells. In addition, binding of mdm2 to N-terminal domain of p53 is directly preventing its transcriptional activation/repression. pRB involved in the formation of a trimeric complex with mdm2 and p53 which inhibits p53 degradation [96]. HSF1 can complex with nuclear p53 and both proteins are cooperatively recruited to p53-responsive genes such as p21, which induces p53-mediated transcription while depletion of HSF1 reduces the expression of p53-responsive transcripts. HSF1 isrequired for optimal expression of p21 and p53-mediated cell-cycle arrest in response to genotoxins and tumor cells [97]. Studies on HSF1 function demonstrate that HSF1 can form complex with DNA damage kinases ATR (Ataxia telangiectasia and Rad3 related) and Chk1 (checkpoint kinase 1) to effect p53 phosphorylation in response to DNA damage and therefore modulate p53-dependent apoptotic pathway.

Role of HSF1 in tumor growth and progression

Amplitude of evidence suggests that HSF1 activation under stress render stressed cells to maintain house keeping function and homeostatic balance and therefore HSF1 protects the cells from dreadful assault of stressor. HSF1 activation is directly correlated to improved cell survival by inhibiting apoptotic machinery in the cells. Furthermore, the ability of HSF1 in promoting cellular adaptation and survival in response to environmental stress has been linked to its Janus kinase-like behavior, which can directly favor oncogenic transformation [98]. Hsf1-/- mice show lower incidence of tumors induced by mutations of the Ras oncogene or a hot spot mutation in the tumor suppressor p53, and they show improved cell survival [98]. HSF1 has been found to be crucial for cellular transformation and tumorigenesis induced by the human epidermal growth factor receptor-2 (HER2), an oncogene responsible for breast tumors aggressiveness. Knockdown of HSF1 has been found to induce growth arrest and senescence of HER2-expressing cells [99]. Moreover, HSF1 is required for the maintenance of the transformed phenotype in established oncogenic cell lines or in breast cancer cell lines with progressive oncogenic states. An elevated protein expression of HSF1 has been reported in the aggressively malignant prostate cancer cell lines such as DU145 and CA-HPV-10 [100], mammary tumor cells [101], gastro-intestinal cancer [102], and glioma and glioblastoma [103].

In breast cancer, the highly malignant factor heregulin beta-1 (HRGβ1) is a secreted factor that binds to c-ErbB-3 and -4 receptors, which provokes the recruitment of c-erbB-2 and receptors heterodimerization. The binding of HRGβ1 to the cell surface induces an increase in HSF1 levels that results in anchorage-independent growth and protection from cisplatin-induced apoptosis mediated by HRGβ1 [101]. One aspect of this process relies on the inhibition of GSK3, a kinase that antagonized HSF1 activation and part of the anti-apoptotic effects of HSF1 seems to operate via activation of the hsp70 promoter and therefore likely to be involved in HSPs synthesis. Increased expression of HSF1 has been considered to drive the suppression of the pro-apoptotic proteins, X-linked inhibitor of apoptosis protein (XIAP)-associated factor-1 (XAF-1) [105], which indicates that HSF1 can impair the apoptotic pathway and favor growth and progression of cancer cells. Moreover, a potential crosstalk takes place with the activity of HSF4, MAPK-induced phosphorylation of which is inhibited by dual specificity phosphatase 26 (DUSP26), thereby negatively affecting its ability to bind DNA in glioma cell lines [106]. Therefore, it is considered that HSF1 promotes tumorigenesis by multiple mechanism(s) such as it promotes tumorigenesis by preserving the functions of those genes which are typically involved in growth and development of cells and regulated by normal genes rather than cancer related genes. Further, tumorigenic phenotype induces the over expression of HSPs synthesis which is independent to cancer related genes.

HSPs as pharmacological targets in cancer: future prospects

The studies reporting the crucial role of HSPs in regulating apoptotic pathways has led the speculation that it could be possible to target for novel cancer therapeutic approach. Recent studies in Bcr-Abl human Leukamia cell lines further suggest that HSPs could be potential targets for cancer therapeutics due to its ability to inhibit apoptotic pathway(s) [107]. As described above, the expression of HSPs is regulated by the activation/deactivation of HSF1 through protein kinase C (serine/threonine kinase). Therefore, it could be possible to inhibit HSPs expression by inhibiting the activation of HSF1 through pharmacological inhibitors of PKC. Therefore, pharmacological inhibition of HSF1 activation seems to be a potential approach to render tumor cells sensitive for programmed cell death disrupt their survival. In agreement with this speculation, pharmacological inhibitors targeting HSPs/HSF1/PKC including flavaniod, Quercetin [108, 109], diterpine [110], triepoxide [111], geldanamycin [112], sanguinarine [113], chelerythrine [117, 118, 120, and 122], RO-31-8220 [114], staurosporine [115], andgeldenamycin and its analogues (17-AAG and 17-DMAG) [116] have been found effective in checking the growth of various tumor cell lines.

Although, geldamycin, a specific inhibitor of hsp90 functions that can block nucleotide binding site of hsp90, results in blocking of interaction between hsp90 and its target proteins [117, 118]. Blocking of hsp90 functions directly affect its association with Ras, p53, and Akt which are frequently dysregulated during tumor progression but play significant role in maintaining cellular transformed state. There are currently 60 trials listed for geldanamycin and dozen trials have been listed for quercetin. HSP90 inhibitors have been demonstrated to increase the heat shock response in the cells because HSF1 is an HSP90 client (indeed, in the early GA analog trials, drug effect was mentioned by HSP70 expression in PBMCs). There is no mention and no tie-in to the potential for altering apoptosis due to increased HSP expression during treatment with HSP90 inhibitors.

Benzophenanthridine alkaloids, chelerythrine and sanguinarine (pseudochelerythrine) derived from Chelidonium majus, (Linneus), and staurosporine, a natural alkaloid originally isolated from the culture broth of bacterium Streptomyces staurosporesa are potent and selective inhibitors of ser/thre kinase such as PKC, which can inhibit HSF1 activation and homotrimerization by inhibiting PKC [119]. whereas has been known to inhibit These pharmacological inhibitors exhibit broad spectrum of biological activities such as anti-microbial, anti-inflammatory [119,120,121] and cell growth-inhibitory effect through the induction of apoptosis in neoplastic cells [122, 123], which suggests their potential application as pro-apoptotic drugs in cancer therapy. The micromolar exposure of triptolide like chelerythrine affects phosphorylation of HSF1, its nuclear translocation, DNA binding ability [124], thereafter and its subsequent transactivating property by a yet unknown mechanism, leading to apoptosis of several tumor cells. Moreover, pharmacological inhibitors of PKC have been suggested effective against certain tumors that are otherwise resistant to standard therapies [125]. Though, there are not enough literature explaining the anti-cancer property of these alkaloids, initial studies revealed that HSF1 is an important target for cancer therapeutics [126], which could be very helpful in designing and developing cost effective, reliable therapeutic drugs against cancers with least side effects. However, detail study is warranted to bring about efficient anti-cancer therapeutic approaches up to the clinical settings.


HSF1 expression is considered to be very crucial for maintaining proto-oncogene status and stressed phenotype of cancerous cells. Reports indicate that HSF1 does not function as a conventional oncogene or tumor suppressor. However, it is not compulsory for HSF1 to involve directly in driving transformation and over expression itself. Heat shock transcription factor-1(HSF1) regulates the expression of HSPs (specifically hsp70) under stress conditions. It is transcriptional event acting at the gene activation level to renovate the normal protein folding in cellular milieu and modulate core cellular processes controlling apoptosis and cell proliferation. Harmful assaults triggered the phosphorylation of protein kinase (PKC) which further activates HSF1translocation and its nuclear migration leading HSF1 homotrimerization and its binding to DNA resulting in elevated expression of HSPs (hsp70 in particular). However, a number of successful clinical studies suggest that HSPs can be used as novel molecular target for pharmacological and therapeutics interventions both to prevent and to cause apoptosis. Moreover, some considerations must be taken when HSPs interact with different pro-apoptotic protein(s) such as Bax, Bcl-Xs and play an essential role in maintaining cellular homeostasis. Further, the pro-apoptotic role of HSPs are balanced and usually overcome by the well known Hsp-induced cytoprotection. Cellular balance is not only a key function in regulating cell death or survival but also serves as a switch between the two forms of cell death, apoptosis and necrosis. Activated HSF1 enhances cell survival and strengthen cytoskeleton even in drastic imbalance of home keeping, intracellular signalling, profound alteration in DNA protein interaction and energy metabolism during stress or malignant transformation/tumor progression. Therefore, HSF1 could be a good candidate for enhanced survival of organisms those are exposed to tumors and malignancies thereby reducing the chance of tumor progression. Curiosity in the pharmacological inhibition of the tumor induced apoptosis has already led to the identification of several indirect inhibitors of HSF1 as discussed previously as above text. However, detail account of studies with this respect remains to be studied. It could be translated into efficient and effective cancer therapeutic regimen. Therefore, regarding the deployment of new potential therapeutics targeting HSF1 would be more innovative as it target a specific regulatory status, allowing a restrictive effect on designated signalling pathways. We hope that the review will help the reader to organize the knowledge on HSF1, HSPs and apoptosis and thereafter provide some clues about the excitement and happiness we have working in this field.