In all organisms, heat-shock proteins (HSPs) provide an ancient defense system. These proteins act as molecular chaperones by assisting proper folding and refolding of misfolded proteins and aid in the elimination of old and damaged cells. HSPs include Hsp100, Hsp90, Hsp70, Hsp40, and small HSPs. Through its substrate-binding domains, Hsp70 interacts with wide spectrum of molecules, ranging from unfolded to natively folded and aggregated proteins, and provides cytoprotective role against various cellular stresses. Under pathophysiological conditions, the high expression of Hsp70 allows cells to survive with lethal injuries. Increased Hsp70, by interacting at several points on apoptotic signaling pathways, leads to inhibition of apoptosis. Elevated expression of Hsp70 in cancer cells may be responsible for tumorigenesis and for tumor progression by providing resistance to chemotherapy. In contrast, inhibition or knockdown of Hsp70 reduces the size of tumors and can cause their complete regression. Moreover, extracellular Hsp70 acts as an immunogen that participates in cross presentation of MHC-I molecules. The goals of this review are to examine the roles of Hsp70 in cancer and to present strategies targeting Hsp70 in the development of cancer therapeutics.
Programmed cell death/apoptosis is a genetically conserved phenomenon involved in many biological processes including reconstruction of multicellular organisms and elimination of old or damaged cells. It is regulated by the activation/deactivation of PKC in response to exogenous and endogenous stimuli. PKC is activated under stress by a series of downstream signaling cascades, which ultimately induce HSF1 activation, which results in overexpression of heat shock proteins. Overexpression of heat shock proteins interferes in the apoptotic pathway, while their blocking results in apoptosis. Therefore, HSF1 could be a novel therapeutic target against a variety of tumors. Several pharmacological inhibitors of PKC have been demonstrated to exert inhibitory effects 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 are still unknown or in their infancy. Therefore, an attempt has been made to delineate the precise role of HSF1 in the regulation of apoptosis and its prospects in cancer therapeutics.
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