Heat Shock Proteins Promote Cancer: It's a Protection Racket

Abstract

Heat shock proteins (HSP) are expressed at high levels in cancer and form a fostering environment that is essential for tumor development. Here, we review the recent data in this area, concentrating mainly on Hsp27, Hsp70, and Hsp90. The overriding role of HSPs in cancer is to stabilize the active functions of overexpressed and mutated cancer genes. Thus, elevated HSPs are required for many of the traits that underlie the morbidity of cancer, including increased growth, survival, and formation of secondary cancers. In addition, HSPs participate in the evolution of cancer treatment resistance. HSPs are also released from cancer cells and influence malignant properties by receptor-mediated signaling. Current data strongly support efforts to target HSPs in cancer treatment.

Figure 1. The Basics of Hsp70 Chaperoning

(a) Heat shock protein 70 (Hsp70) contains two main functional domains, including a peptide-binding domain that recognizes unfolded client proteins and an ATPase domain that can utilize the energy stored in ATP for the folding reaction (above). (b) Thus, the Hsp70 and ATP can promote protein folding (below).(c) Hsp70 associates with unfolded proteins that are themselves recruited by J domain co-chaperones (JDP). Binding of the client protein then triggers the intrinsic ATPase domain of Hsp70 to hydrolyze ATP, resulting in a higher affinity association of ADP-bound Hsp70 with the client. Client release from Hsp70 is triggered by co-chaperones such as HSP-BP1 (Heat Shock Protein-Binding Protein 1) and Bag1 (BCl2-associated athanogene 1). These proteins mediate dissociation of ADP from Hsp70, followed by the binding of ATP. ATP-bound Hsp70 has a reduced affinity for the client that can now dissociate in a more folded conformation.

Figure 2. HSPs in Cancer Signaling

(A) We depict potentially oncogenic proteins (rectangles) being suppressed in normal cells by regulatory proteins (oval, triangle). (B) Potentially oncogenic changes including mutation (pink parallelogram) or increased expression (multiple blue rectangles) fail to transform cells in the absence of elevated HSPs due to insufficient chaperoning power. These mutated and overexpressed oncoproteins are depicted as then undergoing proteasome-mediated degradation. (C) Elevated levels of chaperones (green ovals) permit transformation by stabilizing the mutated or hyperexpressed oncogenic proteins and permitting tumor growth. Cells with elevated HSP levels as in (C) can be reverted to those with a failed oncogenic change as in (B), with oncogene degradation, by chaperone antagonism using drugs such as Hsp90 inhibitors (not shown).

Figure 3. Hsp90 enhances the heregulin-HER3 Signaling Cascade

Heregulin binds to its receptor and launches growth-promoting signaling through the Erk (left), src (far left) and Akt (right) branches. Numerous high affinity partners for Hsp90 (white circle) exist along these pathways, indicating the long reach of Hsp90 in cancer signaling. These pathways can be blocked by Hsp90 inhibitors at each individual Hsp90 chaperoned step, leading to multitargeted cancer therapy.

Figure 4. Elevated levels of HSF1 and HSPs promote renewal of tumor-initiating cancer stem cells

HSPs and HSF1 interact with effectors of CSC renewal and reinforce stemness in a non-canonical manners. Hsp90 and HSF1 promote stemness by, respectively, the STAT3 and β-catenin CSC pathways while Hsp27 promotes stemness through activating NFκB. Expanded populations of CSC then initiate primary and metastatic tumor growth. CSC divide either symmetrically to produce CSC daughter cells or asymmetrically to produce one daughter CSC and one daughter that is a progenitor cell capable of forming different types of tumor tissue. We depict CSCs with a spindle-shaped mesenchymal morphology and NSCs, formed by asymmetric division in the tumor with a more epithelial-type, polygonal morphology.

Figure 5. Intracellular and extracellular HSPs in cancer

HSPs are released from tumor cells and can act in an autocrine manner on the secreting cancer cell. Here, we show an extracellular HSP binding a receptor and stimulating cancer signaling. In addition, extracellular HSPs may also function in a paracrine manner in the milieu, binding to other tumor cells, to immune cells such as macrophages, and to vascular endothelial cells. Extracellular HSPs may thus influence tumor immunity, invasion and metastasis and angiogenesis. Blue ovals are cell nuclei.