HSP90 inhibitors induce desensitization of EGF receptor via p38 MAPK-mediated phosphorylation at Ser1046/1047 in human pancreatic cancer cells

Abstract

Abstract. 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 desensitization 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-dimethylaminoethylamino-17-demethoxy-geldanamycin (17-DMAG). In KP3 cells, 17-AAG induced activation of either p44/p42 mitogenactivated 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.

UVC Radiation Induces Downregulation of EGF Receptor via Phosphorylation at Serine 1046/1047 in Human Pancreatic Cancer Cells

“…We have previously reported that HSP90 inhibitors as well as (-)-epigallocatechin gallate downregulates EGFR via phosphorylation at S1046/7 by p38 MAPK in human colon and pancreatic cancer cells (33,35). In addition, there is accumulating evidence that activation of p38…”

HSP90 inhibitors potentiate PGF2α-induced IL-6 synthesis via p38 MAP kinase in osteoblasts

“…Therefore, inhibition of HSP90 functions has become as one of the leading strategies for anticancer chemotherapeutics [4,5]. In our previous study [6], we have demonstrated that HSP90 inhibitors such as geldanamycin [7], 17-allylamino-17demethoxy-geldanamycin (17-AAG) [8] and 17-dimethylamino-ethylamino-17-demethoxy-geldanamycin (17-DMAG) [9], cause epidermal growth factor receptor (EGFR) desensitization in human pancreatic cancer cells, and that the activation of p38 mitogen-activated protein (MAP) kinase induced by HSP90 inhibitors regulates the desensitization of EGFR via its phosphorylation at Ser1046/7. HSP90 inhibitors, by interfering the N-terminal domain ATP binding site of HSP90, cause the destabilization and eventual degradation of HSP90 client proteins, and then lead to inhibit ATP-dependent HSP90 chaperone activity [10].…”

Synergistic Antitumor Activity of Cetuximab and Namitecan in Human Squamous Cell Carcinoma Models Relies on Cooperative Inhibition of EGFR Expression and Depends on High EGFR Gene Copy Number

“…In the present study, we found that downregulation of EGFR induced by namitecan as well as by cetuximab treatment correlated with the internalization and increased ubiquitination of EGFR, which occurred independently of c-Cbl, an ubiquitin ligase responsible for EGFR degradation after EGF binding (5,31,33). It has previously been reported that other drugs induce downregulation of EGFR without the requirement of c-Cbl binding (34,35,(41)(42)(43)(44). In particular, epigallocatechin gallate and 17-N-allylamino-17-demethoxygeldanamycin cause EGFR downregulation via phosphorylation at Ser1046/1047 by p38 MAPK in different tumor cell lines (42).…”

“…It has previously been reported that other drugs induce downregulation of EGFR without the requirement of c-Cbl binding (34,35,(41)(42)(43)(44). In particular, epigallocatechin gallate and 17-N-allylamino-17-demethoxygeldanamycin cause EGFR downregulation via phosphorylation at Ser1046/1047 by p38 MAPK in different tumor cell lines (42). Although phosphorylation of serine residues and of Tyr1045 is essential for EGFinduced receptor ubiquitination (32, 41), Oksvold and colleagues (45) found that only the serine residues are critical for EGFR internalization and degradation.…”