Heat Shock Proteins: Their Role in Tumor Development and Their Therapeutic Applications Against Cancer

Abstract

Exposure of cells to conditions of environmental stress (e.g. Heat shock) results in the inducible expression of heat shock proteins that function as molecular chaperones or proteases. Heat shock proteins have been classified into six major families according to their molecular size: Hsp100, Hsp90, Hsp70, Hsp60, Hsp40, and small heat shock proteins. Heat shock proteins (HSPs) function by inducing an ATPase-coupled structural change, followed by interactions with diverse co-chaperones and over 200 client proteins implicated in many critical signaling networks. These highly expressed HSPs participate in the onset and progression of several human diseases including cancer, and their connection with tumorigenesis has facilitated research and clinical trials related to targeting HSPs as a novel anti-tumor therapy. The predominant mechanism of chaperone inhibition is through either disruption of the HSP association with client protein or an altered binding state that ultimately leads to proteasome-mediated degradation. Importantly, chaperone inhibition results in the degradation of several client proteins that play critical roles in many of the pathways known as the Hallmarks of Cancer, such as proliferation, angiogenesis, invasion, metastasis, and drug resistance. Hypoxia and other stressful stimuli induce HIF expression as well as subsequent cellular response, resulting in a cascade of signaling events that induce VEGF expression and angiogenesis. Importantly, several critical mediators in this angiogenic signaling pathway, including HIF, VEGF-receptor and IL-8/NF-κB are dependent upon Hsp90 for their function. Given that HSP is required for activation of VEGFR, PKB, and NFκB, HSP inhibitors can be employed to target multiple signaling molecules of angiogenesis pathway, as demonstrated by the potent suppression of VEGF and NO release both in vitro and in vivo with the overall outcome of inhibiting tumor angiogenesis. HSPs also participate in invasion and metastasis of tumor so the inhibition of HSPs through inhibiting client proteins can also be used as complementary to tumor therapy.

Keywords: Angiogenesis, heat shock proteins, invasion, metastasis, tumor, tumor therapy