Targeting GRP75 improves HSP90 inhibitor efficacy by enhancing p53-mediated apoptosis in hepatocellular carcinoma.
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.
Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China.
Weiwei
W
Guo
Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China.
Lichong
L
Yan
Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China.
Ling
L
Yang
Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China.
Xiaoyu
X
Liu
Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China.
Qiukai
Q
E
Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China.
Peiye
P
Gao
Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China.
Xiaofei
X
Ye
Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China.
Wen
W
Liu
Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China.
Ji
J
Zuo
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones / Q000494:pharmacology / Q000627:therapeutic use; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology / Q000627:therapeutic use; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D021381:Protein Transport / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D016227:Benzoquinones; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D008565:Membrane Proteins; D011725:Pyridines; D013844:Thiazoles; D016159:Tumor Suppressor Protein p53; C018551:glucose-regulated proteins; C112765:tanespimycin; C097880:MKT 077