The Regulation Of Apoptosis By Heat Shock Factor Biology Essay

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Programmed cell death/Apoptosis is a genetically conserved common 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 into over expression of HSPs. Over-expression 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 significant inhibitory effect on the activation of HSF1 and therefore induce apoptosis of tumor cells. However, the studies regarding the role of these 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 well known phenomenon by which a cell will actively 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 one another [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 causing an inflammatory response (Figure 1) apoptosis might be (i) caused by the same pathophysiological exposures and (ii) prevented by anti-apoptotic mechanisms, and might be transformed from one form to the another.

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 apoptosis and necrosis exhibit morphological altered expression of some common biochemical events described as the apo-necrosis [3]. In addition, two factors that will induce change in ongoing apoptotic pathway into necrotic pathway which reduces the availability of cleaved caspases and intracellular ATP pool [4, 5]. Therefore, the fate of cells depends on the nature of signal either 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 into degenerative disorder, cancer and autoimmune disease. Therefore, organisms require physiological defense mechanism(s) to cope up with the 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 to prevent cell death during 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) which have been characterized by the involvement of a number of apoptogenic proteins. However, there are several common proteins which involved in both extrinsic as well as 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 responsible to initiate intrinsic apoptotic pathway by integration of 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 affect positively to death progrms (Figure 2). These happening 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, 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 binds to Apaf-1 and procaspase-9 forming a multi-protein complex structure known as "apoptosome" which consist 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 Asp 315 to generate the processed p35/p12 form of the enzyme (C9-p35/p12) that recruit and activates the effector procaspase-3. For the enzymatic activity of caspase-9, it must remain bound to the complex (apoptosome) to show significant proteolytic activity. Activation of effector caspases and correspondingly mutation in p53 status 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 the member of Bcl2 family proteins either pro-apoptotic or anti-apoptotic. However the mechanism(s) of action remain a question of some debate [17]. The 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 pro-survival to pro-apoptotic 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 Bax, cl-Xs, Bid Bad, Bim and Blk respectively. These proteins are very 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 consist 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 signals amplification of apoptotic events to intracellular microenvironment. 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. FADD molecules 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 consist a second death fold motif, a DED which help in binding of caspases monomer to N-terminal DED domains in another homophilic interaction, resulting a localized interaction of caspases-8. Currently, a death-inducing signalling complex (DISC) is formed, resulting self-cleavage of inactivated caspase-8 [25]. Activated caspase-8 induces apoptosis either directly activating caspase-3 or through truncated Bid protein.

Comparing two classical apoptotic pathways (intrinsic and extrinsic apoptotic pathway), receptor mediated apoptotic pathway associated with extrinsic apoptotic pathway seems to be more recently evolved form of activating 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-induced caspase-independent apoptosis through single strand break of DNA [26]. Moreover, ceramides are signal mediators sphingolipid, involved in the regulation of growth, differentiation and apoptosis.

Protein Kinase C is a family of serine/threnine kinase plays an essential role in proliferation, differentiation and apoptosis. Activation of PKC isoforms induce changes in their sub-cellular localization, triggered by phospholipid diacylglycerol (DAG) and Ca++ ions [27]. Activated PKC integrates downstream signal for other kinases phosphorylation [28, 29]. However, other forms of PKC can activate 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 proteins, which transduces apoptotic signals for its execution. Further, PKC activation has been considered to up-regulates expression of anti-apoptotic factors such as Bcl2, Bcl-xl, Bcl-x, Bcl-w, BAG, 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 and greater the ratio of pro-apoptotic proteins resulted apoptosis. Studies indicate that proteins associated with apoptosis might be inside the mitochondria and worktogather with pro-survival member of Bcl2 family proteins, resulting change in mitochondrial membrane potential, release of cyt-c and subsequent activation of caspase-9. Activated caspase-9 further induces the cleavage of effector caspases (Caspase-3) which further cause apoptosis [31]. In addition, concentration of Ca++ may alter p53 function, which triggered DNA fragmentation and therefore death of target cells. On the other hand, inactivated p53 (high Ca++ concentration results in p53 inactivation) results in HSF1 nulear migration and its activation leading over expression of HSPs (heat shock proteins) which might be very useful in the regulation of cellular environment and apoptosis.

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 HSF1-HSF4 [35-37]. HSF1 is a master transcription factor, responsible for heat inducible expression of HSPs [38, 39]. 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 not play more essential 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 which 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) increase 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]. Enhanced expression of HSPs plays a vital role in maintaining cellular homeostasis against stresses, due to its chaperone function [42, 43]. In contrast, failure of their chaperone function results 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 maintaining cellular homeostasis, serving more dynamic proteins, strong affinity extentions 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. [49, 50]. Further, small HSPs (sHSP) family members are very well known to their preventive role of actin filaments and helpful for cell survival [51, 52]. Recent reports suggest that anti-hsp27 antibodies induce neuronal apoptosis by disrupting actin filaments [53]. The hsp70 homologue, and hsp105, protects 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 genes that drive programmed cell death. Heat responsible protein 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. A recent report 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 radiation. 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. Hsp90 enhances apoptosis in U937 cells when treated with both TNF-α and cycloheximide but not when exposed to TNF-α, cycloheximide or UV B radiation [59].

Cell death is 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. 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 stimuli [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 report suggests that HSF1 has profound role in cell viability,apoptosis, growth, development and differentiation. Yeast HSF 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 basal HSP gene expression [67]. Interestingly, the Drosophila HSF 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 activation of caspase-dependent apoptotic pathway. Caspase-dependent apoptotic cell death 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 for heat shock factor (HSF-regulated), BAG3, 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 over expression of Bcl2 family proteins associated with over expression of HSPs through a number of heat shock inducing agents [75]. However, the expression of BAG-1 has been detected significant 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, some researchers have been investigated that HeLa cells are relatively insensitive to Fas-mediated killing, but over-expressed a constitutively activated form of HSF1 (HSF1+) directly sensitize the cells to Fas-mediated killing [81].

It has been considered that HSPs play a very crucial role in preventing the cells from heat shock and thermal stresses through the activation of a transcription factor HSF1. Reports on HSF1 functions demonstrate that stress induce activation of HSF1 leads over expression of heat responsible proteins such as hsp70 and hsp90. In contrast, blocking of HSF1 function by specific inhibitor/non-specific inhibitor of serine/threonine kinase reduce the expression of HSPs which might be helpful for further execution of apoptosis[82, 83].

HSF1 in p53 regulation

Protein 53 (p53) is a tumor suppressor protein encoded by the TP53 gene located on short arm of chromosome 17 in human at 17p13.105-p12. It 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". Recent, studies have been shown that p53 induces cell growth arrest or apoptosis under cellular stress, which indicates that it is an important protein that is directly or indirectly involved in the mechanism of apoptosis. Wild type p53 is involved in the induction of apoptosis in the cells under stress by interfering the homotrimerization and formation of HSE-HSF1 complex of HSF1 [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 their ability to bind DNA and can also induce alterations in p53 functions during tumorigenesis. p53 exhibits pro-apoptotic nature which is associated to its different transactivating approaches in apoptosis. Such type 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 [90-94]. Moreover, recent reports on knock in mice suggest that mice were expressing p53 transcriptionally dead because DNA binding property of p53 are defective in apoptosis [95], suggesting in vivo evidence that transactivation of p53 is very essential for p53 to induce apoptosis of normal cells. In addition, targeting p53 for its degradation, the binding of mdm2 to the amino-terminal domain of p53 directly prevents both transcriptional activation and repression by p53, pRB, and can enter into a trimeric complex with mdm2 and p53 to inhibits the degradation of p53 [96]. HSF1 can complex with nuclear p53 and both proteins are cooperatively recruited to p53-responsive genes such as p21 and enhance p53-mediated transcription, whilst depletion of HSF1 reduces the expression of p53-responsive transcripts. HSF1 is also required for optimal p21 expression and p53-mediated cell-cycle arrest in response to genotoxins [97]. Studies on the HSF1 function has been suggested 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 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 with the enhancement of 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-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 involves HSPs. In gastro-intestinal cancers, HSF1 activation leads to the induction of the hsp70 co-chaperone BAG-3, which stabilizes the ratio of pro-survival to pro-apoptotic Bcl2 family members, and support colon cancer cell survival during pro-apoptotic stress [104]. Increased expression of HSF1 has been found to drive the repression 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 can precisely concluded that HSF1 promotes tumorigenesis by multiple mechanisms either by preserving function of those genes which are typically involved in the growth and development of normal cells that are regulated by normal genes rather than typical cancer related genes dependent to HSPs synthesis or directly affecting transcriptional regulation independent to HSPs synthesis.

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 translate into a novel approach of cancer therapeutics. Recent studies in Bcr-Abl human Leukamia cell lines suggest that HSPs would be potential targets for cancer therapeutics due to its ability to inhibit apoptotic pathway(s) both upstream and downstream [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 block/suppress HSPs expression by deactivating HSF1 through the use of pharmacological inhibitors of PKC. Though, the pharmacological manipulation of HSF1 functions may likely explain the opportunities either to render tumor cells sensitive to death programmed through chemotherapeutics, UV radiation, alternatively and selectively disrupt their survival. Moreover, several pharmacological inhibitors targeting HSPs have been studied, which includes flavaniod, Quercetin [108, 109], diterpine [110], triepoxide [111], geldanamycin [112], sanguinarine [113], chelerythrine [117, 118, 120, and 122], RO-31-8220 [114], staurosporine [115], and an analog, 17AAG [116], 17-DMAG [116].

Although, Geldamycin, a specific inhibitor of hsp90 functions which can block nucleotide binding site of hsp90 resulting no interaction between hsp90 and its associated target proteins [117, 118]. Blocking of hsp90 functions in ATP-dependent manner 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. Whether the mode of action might be applied for blocking the interation between other member of HSps family and their target proteins has to be investigating in details. Indeed it remains an exciting possibility that pharmacological strategies of HSP-modulation may indication of novel approach in cancer therapeutics.

Benzophenanthridine alkaloids chelerythrine, and sanguinarine (pseudochelerythrine) derived from Chelidonium majus, L. (and other Papaveraceae plants), and staurosporine, a natural alkaloid originally isolated from the culture broth of bacterium Streptomyces staurosporesa by Omura et al. have been known to inhibit HSF1 activation and homotrimerization by inhibiting PKC [119]. These pharmacological inhibitors exhibit broad spectrum of biological functions such as anti-microbial, anti-inflammatory [119,120,121] and cell growth-inhibitory effect through the induction of apoptosis in neoplastic cells [122, 123], suggesting their potential application as pro-apoptotic drugs in cancer therapy. The micromolar exposure of triptolide like chelerythrine affects phosphorylation of HSF1, nuclear translocation, and its DNA binding ability [124], thereafter its transactivating property by a yet unknown mechanism, leading to apoptosis of several tumors and their cell lines. 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 to explain the biological functions of these alkaloids, initial studies revealed HSF1 as 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 upto the clinical settings.


Heat shock transcription factor-1(HSF1) regulates the expression of HSPs (specifically hsp70) under stressful conditions. It is transcriptional event acting at the gene activation level to renovate the normal protein folding in cellular milieu and modulate cellular process controlling apoptosis and cell proliferation. Harmful assaults triggered the phosphorylation of protein kinase (PKC) which further activates HSF1translocation leading HSF1 homotrimerization and its binding to DNA results in elevated expression of HSPs (hsp70 in particular). HSPs can interact with different pro-apoptotic protein(s) such as Bax, Bcl-Xs and play an essential role in stabilizing cellar state. Activated HSF1 prolonged 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, the role of HSF1 in enhancing the survival of organism exposed to tumorigenesis might be a unique cancer therapeutic opportunity for tumor regression. Curiosity in the pharmacological inhibition of the tumor induced apoptosis has already led to the identification of several inhibitors of HSF1 such as flavaniod, quercetin, diterpine, triepoxide, geldanamycin, sanguinarine, chelerythrine, RO-31-8220, staurosporine, and an analog, 17AAG, 17-DMAG. However, detail account of studies in this respect remains to be studied that could be translated into efficient and effective cancer therapeutics.