HSP90 inhibitors induce desensitization of EGF receptor via p38 MAPK-mediated phosphorylation at Ser1046/1047 in human pancreatic cancer cells.
Heat shock protein (HSP) 90 is known to be a molecular chaperone whose association is required for the stability and function of oncogenic protein including epidermal growth factor receptor (EGFR) that promotes cancer cell growth. Therefore, HSP90 is a promising target for therapy against cancer including in the pancreas, some of which are highly dependent on EGFR. We investigated the effects of HSP90 inhibitors on cytotoxicity and desensitization of EGFR in human pancreatic cancer cells (KP3, BxPc3 and AsPc1). 17-allylamino-17-demethoxy-geldanamycin (17-AAG), an inhibitor of HSP90, caused de-sensitization of EGFR in a time-dependent manner, concurrently inducing phosphorylation of EGFR at Ser1046/1047 (Ser1046/7), a site which plays an important role in EGFR desensitization in these pancreatic cancer cells. We also found similar effects in KP3 cells treated with other HSP90 inhibitors, geldanamycin and 17-dimethylamino-ethylamino-17-demethoxy-geldanamycin (17-DMAG). In KP3 cells, 17-AAG induced activation of either p44/p42 mitogen-activated protein kinase (MAPK) or p38 MAPK. Interestingly, whereas the inhibition of p44/p42 MAPK attenuated neither phosphorylation of EGFR at Ser1046/7 nor desensitization of EGFR, the phosphorylation at Ser1046/7 induced by 17-AAG was markedly attenuated by the inhibition of p38 MAPK, indicating that p38 MAPK induced this phosphorylation. Moreover, the inhibition of p38 MAPK significantly attenuated 17-AAG-induced EGFR desensitization. These results strongly suggest that EGFR phosphorylation at Ser1046/7 via activation of p38 MAPK induced by HSP90 inhibitors plays a pivotal role in EGFR desensitization in human pancreatic cancer cells.
Adachi
Seiji
S
Department of Gastroenterology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan. seijiadachi0123@gmail.com
Yasuda
Ichiro
I
Nakashima
Masanori
M
Yamauchi
Takahiro
T
Yamauchi
Junichi
J
Natsume
Hideo
H
Moriwaki
Hisataka
H
Kozawa
Osamu
O
D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones / Q000494:pharmacology*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C112765:tanespimycin; D066246:ErbB Receptors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases