A novel Hsp90 inhibitor to disrupt Hsp90/Cdc37 complex against pancreatic cancer cells.
Pancreatic cancer is an aggressive disease with multiple biochemical and genetic alterations. Thus, a single agent to hit one molecular target may not be sufficient to treat this disease. The purpose of this study is to identify a novel Hsp90 inhibitor to disrupt protein-protein interactions of Hsp90 and its cochaperones for down-regulating many oncogenes simultaneously against pancreatic cancer cells. Here, we reported that celastrol disrupted Hsp90-Cdc37 interaction in the superchaperone complex to exhibit antitumor activity in vitro and in vivo. Molecular docking and molecular dynamic simulations showed that celastrol blocked the critical interaction of Glu33 (Hsp90) and Arg167 (Cdc37). Immunoprecipitation confirmed that celastrol (10 micromol/L) disrupted the Hsp90-Cdc37 interaction in the pancreatic cancer cell line Panc-1. In contrast to classic Hsp90 inhibitor (geldanamycin), celastrol (0.1-100 micromol/L) did not interfere with ATP binding to Hsp90. However, celastrol (1-5 micromol/L) induced Hsp90 client protein degradation (Cdk4 and Akt) by 70% to 80% and increased Hsp70 expression by 12-fold. Celastrol induced apoptosis in vitro and significantly inhibited tumor growth in Panc-1 xenografts. Moreover, celastrol (3 mg/kg) effectively suppressed tumor metastasis by more than 80% in RIP1-Tag2 transgenic mouse model with pancreatic islet cell carcinogenesis. The data suggest that celastrol is a novel Hsp90 inhibitor to disrupt Hsp90-Cdc37 interaction against pancreatic cancer cells.
Zhang
Tao
T
Division of Pharmaceutics, College of Pharmacy, The Ohio State University, 500 West 12th Avenue, Columbus, OH 43210, USA.
Hamza
Adel
A
Cao
Xianhua
X
Wang
Bing
B
Yu
Shuwen
S
Zhan
Chang-Guo
CG
Sun
Duxin
D
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018833:Chaperonins / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D053978:Pentacyclic Triterpenes; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011485:Protein Binding; D014315:Triterpenes / Q000737:chemistry / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; C498362:CDC37 protein, human; D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; C476884:HOPX protein, human; D018841:HSP90 Heat-Shock Proteins; D018398:Homeodomain Proteins; D053978:Pentacyclic Triterpenes; D061988:Proteasome Inhibitors; D014315:Triterpenes; D025521:Tumor Suppressor Proteins; D000255:Adenosine Triphosphate; D046988:Proteasome Endopeptidase Complex; D018833:Chaperonins; C050414:celastrol