Heat Shock Protein 70 Neutralization Exerts Potent Antitumor Effects in Animal Models of Colon Cancer and Melanoma

Abstract

When overexpressed, the stress protein heat shock protein 70 (HSP70) increases the oncogenic potential of cancer cells in rodent models. HSP70 also prevents apoptosis, thereby increasing the survival of cells exposed to a wide range of otherwise lethal stimuli. These protective functions of HSP70 involve its interaction with and neutralization of the adaptor molecule apoptotic protease activation factor-1, implicated in caspase activation, and the flavoprotein apoptosis-inducing factor (AIF), involved in caspase-independent cell death. We have shown previously that a peptide containing the AIF sequence involved in its interaction with HSP70 (ADD70, amino acids 150-228) binds to and neutralizes HSP70 in the cytosol, thereby sensitizing cancer cells to apoptosis induced by a variety of death stimuli. Here, we show that expression of ADD70 in tumor cells decreases their tumorigenicity in syngeneic animals without affecting their growth in immunodeficient animals. ADD70 antitumorigenic effects are associated with an increase in tumor-infiltrating cytotoxic CD8 + T cells. In addition, ADD70 sensitizes rat colon cancer cells (PROb) and mouse melanoma cells (B16F10) to the chemotherapeutic agent cisplatin. ADD70 also shows an additive effect with HSP90 inhibition by 17-allylamino-17-demethoxygeldanamycin in vitro. Altogether, these data indicate the potential interest of targeting the HSP70 interaction with AIF for cancer therapy.

A novel, small molecule inhibitor of Hsc70/Hsp70 potentiates Hsp90 inhibitor induced apoptosis in HCT116 colon carcinoma cells

“…Several reports suggest that down regulating Hsp70 was sufficient to induce tumor specific death [12,15,16] while others suggest that either Hsc70 or Hsp70 is dispensable for tumor cell viability [21,30]. Our own data, in which either Hsc70 or Hsp70 was depleted in a panel of ten solid cancer cell lines support the later observation (data not shown).…”

“…However, these chaperones have been shown to contribute to cancer cell survival via multiple anti-apoptotic functions [6,9] and increased expression of Hsp70 has been implicated in resistance to cytotoxic chemotherapeutics [10,11]. Selective knockdown of Hsp70 by both RNAi and antisense results in cell arrest and death in a variety of cancer cell lines [12][13][14][15]. Furthermore, localised tumor cell application of Hsp70 antisense expressing adenovirus reduced the growth of orthotopic glioblastoma and breast carcinoma, as well as sub-cutaneous colon cancer xenografts in mice [16].…”

Elevated Serum Levels of Heat Shock Protein 70 Are Associated with Breast Cancer

“…The search for inhibitors of HSP70 has dramatically increased over the last two years. One interesting observation is that HSP70 inhibition or depletion provokes tumor regression in syngeneic animals by inducing an immune anti-tumor response (Schmitt et al 2006). This immune response might be explained by the inhibiting effect of HSP70 in activating myeloid suppressive cells (Chalmin et …”

Molecular chaperones as regulators of cell death

“…Hsp70 directly binds to AIF and inhibits AIFdependent caspase-independent apoptosis (Ravagnan et al, 2001). A peptide containing the AIF sequence involved in its interaction with Hsp70 induced apoptosis in both rat colon cancer cells and mouse melanoma cells under cisplatin stimuli (Schmitt et al, 2006). Nylandsted et al (2000) reported that Hsp70 inhibited apoptosis in human breast tumor cells, but it was neither dependent on caspases nor on p53, suggesting versatile functions of Hsp70 or the function in the downstream of unknown caspases.…”