Protein Kinase In Cancer Cells Biology Essay


A protein kinase is a kinase enzyme that changes other proteins by chemically adding phosphate groups to them. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins [1]. The gene family encoding protein kinases is the most commonly mutated in human cancer. Moreover, mutated and activated protein kinases have proved to be good targets for the development of new targets for cancer therapies [4]. Evidence has established that several different forms of protein kinase fail to regulate properly in many cancer types, and it has been known that protein kinases play important roles in regulating most cellular functions such as cell growth, apoptosis, DNA damage repair, cell motility, and response to the microenvironment. Now that this is established, this research paper will focus on the potential of protein kinase as a chemotherapeutic target in cancer treatment and highlights recent studies in the development of protein kinase inhibitors in different cancer cells.

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Cancer is a group of diseases characterized by aberrations in cellular growth, proliferation and survival pathways, resulting in tumor formation and uncontrolled expansion of cancer cells [3]. Kinases such as c-Src, c-Abl, mitogen activated protein (MAP) kinase, phosphotidylinositol-3-kinase (PI3K) AKT, and the epidermal growth factor (EGF) receptor are commonly activated in cancer cells, and are known to contribute to tumorigenesis. Many of these occur in the same signaling pathway [2]. Research groups have developed several ways to target these enzymes therapeutically, such as with antibodies or small molecules that block kinase-substrate interaction, or that inhibit the enzyme's adenosine triphosphate (ATP) binding site. A number of kinase inhibitors have therefore already been developed and approved for cancer treatment. The potential for targeting kinases in the treatment of cancer was the theme of the Keystone Symposium "Protein Kinases and Cancer: The Promise of Molecular Based Therapies" recently held in Tahoe City, California [2]. In the opening address, Robert Wittes [2], of the Memorial Sloan-Kettering Cancer Center, New York City, NY, discussed the pros and cons of targeting kinases in cancer patients. Kinase inhibitors designed to block the enzyme's ATP binding site can have broad specificity such as; imatinib not only inhibits the tyrosine kinase c-Abl, but also c-Kit and the platelet-derived growth factor (PDGF) receptor tyrosine kinases. So it can be used to treat many types of tumors associated with activation of these signaling molecules [2].

Emerging as a major player in cell proliferation, survival, motility, and angiogenesis pathways, it is no surprise that Protein kinase has recently received a lot of attention as a potential target in the treatment of many types of cancer.

1. Breast cancer

PKD enzymes were first studied in the context of breast cancer over a decade ago [4]. Despite this early start, the mechanisms through which PKD may contribute to breast cancer progression are not yet clear. Analysis of invasive human breast tumors has revealed that protein Kinase expression is downregulated in infiltrating ductal carcinoma compared to normal breast tissue [5]. In the study " Protein Kinase as a potential new target for cancer therapy" several transcriptional microarray studies of gene expression in normal breast tissue and of early and advanced-stage breast tumors have shown reduction of the protein kinase gene correlating with increased invasiveness and cancer progression [4].

Functionally, studies investigating the role of protein kinase in breast cancer progression have focused on the processes of invasion and adhesion. As early as 1999, Bowden and colleagues [4] described an interaction between protein kinase, paxillin, and cortactin at sites of invadopodia in breast cancer cells. Invadopodia are actin-containing protrusions that extend outward into the extracellular matrix and participate in degradation of the ECM [6]. This interaction, present in invasive breast cancer cells but not in non-invasive lines, suggested that protein kinase may regulate the function or formation of the paxillin/cortactin complex to promote invasion.

Multiple separate studies have strongly supported an opposing role for protein kinase in breast cancer cell invasion and adhesion. Studies by Eiseler and colleagues [5] have shown that invasion in 2D and 3D environments was reduced with expression of a constitutively active protein kinase mutant in breast cancer cells. Based on mechanistic argumentation, it has been suggested that the regulation of adhesion and invasion by PKD1 may be related to MMP expression. MMP is an enzyme that degrades matrix proteins. In breast cancer, MMP in particular has been identified as an indicator of potential malignancy [7]. Thus, it is possible that protein kinase may inhibit breast cancer invasion and metastasis through regulation of MMP expression.

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2. Pancreatic cancer

Ductal adenocarcinoma of the pancreas is a devastating disease with a very low 5-year survival rate (5%) [8]. Studies in pancreatic cancer cells are some of the earliest works indicating a potential role for protein kinase in cancer. In human ductal adenocarcinoma of the pancreas, studies showed that protein kinase is overexpressed compared to normal pancreatic tissues [9].

In pancreatic cancer cell lines, studies on the function of protein kinase have revealed a role in cell proliferation and apoptosis. Another study showed the importance of the role of protein kinase in pancreatic cancer. Researchers showed that treatment with the novel protein kinase inhibitor reduced tumor growth in pancreatic cancer cells [8]. Taken together, these studies reveal the functions of protein kinase in pancreatic cancer cells, and implicate protein kinase as a potential therapeutic target in pancreatic cancer treatment [8,9].

3. Basal cell carcinoma and skin cancer

Basal cell carcinoma (BCC) is an extremely common form of malignant skin cancer [10]. Analysis of BCC lesions showed increased expression of protein kinase when compared with normal epidermis [11]. Furthermore, protein kinase expression in normal epidermis was primarily restricted to the stratum basalis, the proliferative compartment of the epidermis, supporting the concept that protein kinase promotes hyperproliferative disorders of the skin [12].

4. Gastric cancer

Similar to the studies in breast cancer, analysis of protein kinase levels in primary gastric tumors and gastric cancer cell lines has revealed decreased protein. Interestingly, the authors of a recent study "Role of protein kinase D signaling in pancreatic cancer" [13] demonstrated a gradual increase in methylation of the protein kinase promoter in aging, but normal, gastric mucosal tissues. Since the incidence of gastric cancers is positively correlated with age, it is possible that protein kinase silencing may occur early on in the development of gastric cancer. Moreover, the lack of protein kinase may promote the development of metastases, which is a secondary tumour caused by migration of cancer cells to another tissue [13].

Considering the evidence suggesting that protein kinase positively regulates cell survival and proliferation, it is possible that the expression and silencing of protein kinase are concerted events occurring at different stages of tumor development. Thus, the presence of protein kinase may be required for early tumor promoting events such as enhanced survival and proliferation, while silencing of protein kinase may be necessary to allow tumor progression into invasive stages [13, 15].

5. Lung cancer

Very little is known about the role of protein kinase in small cell lung cancer. One study has shown that the protein kinase signaling pathway exists in the cell lines [3]. To date, there have been no reports on protein kinase expression and distribution in actual human tumor samples.

Immunohistochemistry analysis of multiple types of human malignant lymphoma have revealed varying expression of protein kinase and activity [14]. The authors of the study "Protein Kinase as a potential new target for cancer therapy" suggest that protein kinase expression often were very similar to the normal lymph tissue from which the particular tumors were derived. This study suggests that while protein kinase is expressed in many types of lymphoma, it may not be involved in progression of the disease; however, more studies are required to support these conclusions [3].

In conclusion extensive evidence indicates that protein kinase expression is deregulated in multiple cancer types and plays an active role in a variety of cancer-associated biological processes including proliferation, survival, apoptosis, migration, invasion, and angiogenesis, making protein kinase an attractive target for drug development [3]. To date, there have been no reports of genetic protein kinase animal models related to cancer. However, despite this, pharmacological inhibition of protein kinase has now shown to be effective at suppressing growth of pancreatic tumor xenografts [15], which greatly enhances the validity of protein kinase as a chemotherapeutic target.