Targeting GRP75 Improves HSP90 Inhibitor Efficacy by Enhancing p53-Mediated Apoptosis in Hepatocellular Carcinoma

Abstract

Heat shock protein 90 (HSP90) inhibitors are potential drugs for cancer therapy. The inhibition of HSP90 on cancer cell growth largely through degrading client proteins, like Akt and p53, therefore, triggering cancer cell apoptosis. Here, we show that the HSP90 inhibitor 17-AAG can induce the expression of GRP75, a member of heat shock protein 70 (HSP70) family, which, in turn, attenuates the anti-growth effect of HSP90 inhibition on cancer cells. Additionally, 17-AAG enhanced binding of GRP75 and p53, resulting in the retention of p53 in the cytoplasm. Blocking GRP75 with its inhibitor MKT-077 potentiated the anti-tumor effects of 17-AAG by disrupting the formation of GRP75-p53 complexes, thereby facilitating translocation of p53 into the nuclei and leading to the induction of apoptosis-related genes. Finally, dual inhibition of HSP90 and GRP75 was found to significantly inhibit tumor growth in a liver cancer xenograft model. In conclusion, the GRP75 inhibitor MKT-077 enhances 17-AAG-induced apoptosis in HCCs and increases p53-mediated inhibition of tumor growth in vivo. Dual targeting of GRP75 and HSP90 may be a useful strategy for the treatment of HCCs.

Heat shock proteins in hepatocellular carcinoma: Molecular mechanism and therapeutic potential

“…demonstrated that 17‐AAG could sensitize Bcl‐2 inhibitor (−)‐gossypol through inhibiting ERK‐mediated autophagy and Mcl‐1 accumulation in Hep3B and HepG2 cells . Furthermore, 17‐AAG treatment induces the expression of 75 kDa glucose‐regulated protein (GRP75), which in turn decreases the efficacy of HSP90 inhibition on HCC cells . Dual targeting of GRP75 and HSP90 with MKT‐077 and 17‐AAG indicates synergistic effects on tumor growth in vivo .…”

“…Furthermore, 17‐AAG treatment induces the expression of 75 kDa glucose‐regulated protein (GRP75), which in turn decreases the efficacy of HSP90 inhibition on HCC cells . Dual targeting of GRP75 and HSP90 with MKT‐077 and 17‐AAG indicates synergistic effects on tumor growth in vivo . Another HSP90 inhibitor, 17‐(dimethylaminoethylamino)−17‐demethoxygeldanamycin (17‐DMAG), exhibits about two times potency against human HSP90 than 17‐AAG.…”

Structural studies of UBXN2A and mortalin interaction and the putative role of silenced UBXN2A in preventing response to chemotherapy

“…This current study suggests UBXN2A binds to mortalin's protein binding pocket and interferes with mortalin's binding partners (Dundas et al 2005;Gestl and Anne Bottger 2012;Guo et al 2014;Sadekova et al 1997) resulting in inactivation of mortalin oncoprotein in cancer cells. Part of the apoptotic resistance of cancer cells is mediated by activation of WT-mortalin in cancer cells, including osteosarcoma (Wadhwa et al 2015).…”

“…We hypothesized that UBXN2A binding to mortalin's binding pocket can also disrupt mortalin's interaction with partners, antagonize oncogenic function of mortalin, and eventually induce cell cytotoxicity in cancer cells. Overexpression of mortalin correlates with a higher proliferation rate, colony forming efficacy, motility, and tumor forming capacity; poor survival; and increased resistance to therapies (Dundas et al 2005;Gestl and Anne Bottger 2012;Guo et al 2014;Sadekova et al 1997). …”

Hsp70 inhibitors: Implications for the treatment of colorectal cancer

“…MKT‐077 could bind to the NBD tail of mortalin resulting in tertiary structural modifications in the protein, attenuating its chaperone function. It also could destabilize the ATP‐bound conformation of mortalin . Moreover, it has been found that MKT‐077 occupies a pocket adjacent to the nucleotide‐binding cleft of Hsc70 and exerts a pseudo‐ADP bound conformer .…”