Designing of Anti-Cancer Drug Targeted to Bcl-2 Associated Athanogene (BAG1) Protein

Cancer is a disease of uncontrolled cell growth in tissues. This growth may lead to metastasis, which is the invasion of adjacent tissue and infiltration beyond the site of initiation. Cancer is initiated by activation of oncogenes or inactivation of tumor suppressor genes. Nearly 10-30% of all adenocarcinomas are due to the mutations in the K-ras protooncogene. [1] Function and regulation of Bcl-2 proteins depends upon their interaction with other non-family member proteins, including NIP1, NIP2, NIP3, p53 BP2, Raf-1, CED-4, calcineurin, R-Ras and Bag-1 to form homo and hetero dimmers.[21] Bag1 belongs to the Bcl2 associated athanogene (BAG) family of multifunctional proteins. This widely expressed protein interacts with a number of signalling molecules (including Bcl2, HGF receptor and Raf1) as it regulates signalling molecules in pathways involving cell survival, growth and differentiation. [13] Bcl2 associated athanogene (BAG1) protein is involved in regulation of the Ras/Raf signal transduction pathway. Of particular relevance to tumour cells, BAG-1 interacts with the anti-apoptotic BCL-2 protein, various nuclear hormone receptors the 70 kDa heat shock proteins, Hsc70 and Hsp70; and serine/threonine kinase. Raf-1 which plays an important role in MAPK pathway.[2][3][4] Recent studies have shown that BAG-1 expression is frequently altered in malignant cells, and BAG-1 expression may have clinical value as a prognostic or predictive marker for various cancer types including breast cancer, prostate cancer and lung cancer.[6][7][8] (Fig 1) Interaction with chaperones may account for many of the pleiotropic effects associated with BAG-1 over expression. The finding that BAG-1 can independently associate with Raf-1 or Bcl-2 provides at least two mechanisms by which BAG-1 promotes cell survival. [20] Bcl2-associated athanogene (BAG) family proteins participate in a wide variety of cellular processes to regulate growth control pathways, including cell survival (stress response), proliferation, migration, signalling and apoptosis (Fig 2).[2][5][18] This family of cochaperones functionally regulates signal transduction proteins Raf/MEK/ERK and transcription factors important for cell stress responses, apoptosis, proliferation, cell migration and hormone action. In response to stress, they bind to heat shock proteins HSP70/HSC70 coordinating cell growth signals, by down-regulating the activity of serine/threonine kinase, Raf-1, which plays an important role in MAPK pathway. [5][9] The proteins show anti-apoptotic activity and increase the anti-cell death function of BCL-2 induced by various stimuli. Over expression of BAG-1 suppresses activation of caspases and