Heat shock proteins as novel cancer therapeutics: Targeting the hallmarks of cancer

Molecular chaperones, commonly known as heat shock proteins (HSPs), are essential for mammalian cells to maintain homeostasis, and 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. Here, we discuss: (1) the current knowledge of HSPs, particularly studies related to Hsp90-targeted cancer therapy, (2) the targeting of Hsp90-mediated signaling interactions to prevent emergence of core Hallmarks of Cancer, (3) the recent progression of Hsp90 inhibitors in clinical trials. Finally, we propose combinatorial therapy, additional inhibitor discovery, and location-specific inhibition of HSPs as necessary next steps in chaperone-targeted research relevant to cancer therapy. CHAPTER ONE INTRODUCTION The eukaryotic heat shock proteins (HSPs) are a set of the most highly conserved proteins in nature, collectively known as essential and ubiquitous molecular chaperones for their cytoprotective functions during the maintenance of organism homeostasis under both physiological and pathological conditions (Lindquist 1988; Hendrick et al 1993). Mammalian HSPs have also been recognized to play a series of critical roles in tumorigenesis, as well as their function in protein assembly and the prevention of protein misfolding and aggregation under stress conditions. Chaperones are divided into four major families, Hsp90, Hsp70, Hsp60, and Hsp20, according to their relative molecular mass (Calderwood et al 2006; Jego et al 2010), while additional novel families include Hsp110 and Hsp170 (Easton et al 2000). In order to survive under the harsh conditions within the tumor microenvironment, cancer cells typically become dependent on stress-inducible HSPs in order to become refractory to chemotherapy, tolerant to hypoxia, resistant to apoptosis, and to suppress antitumor immunity, all the while acquiring the properties of invasiveness and metastasis during cancer progression. To date, more than 200 HSP client proteins have been identified involving nearly all fundamental cellular activities and processes, including cell growth, proliferation, and cell survival (Jego et al 2010). Interestingly, many cancer-associated proteins have been reported as HSP clients, likely as a mechanism for promoting oncogenic transformation. Therefore, targeting HSPs would result in simultaneous inhibition of multiple signaling pathways responsible for modulation of various events