Abstract
Gastric cancer (GC) remains the fifth most common cancer worldwide. Heat-shock protein 90 (HSP90) has become an attractive therapeutic target in treating cancers, because of its abnormally high expression in cancers. Several successful cases of HSP90 inhibitors capable of inhibiting GC inspired us to try ganetespib, a clinically promising and actively investigated second-generation HSP90 inhibitor in GC treatment. In our study, we show that ganetespib markedly reduced the growth of MGC-803 and also significantly inhibited the growth of SGC-7901 and MKN-28 in a dose-dependent manner. It induced G2/M cell-cycle arrest and apoptosis in all three cell lines, together with the related markers affected significantly. Mechanistically, ganetespib caused pronounced decrease of expression of classic HSP90 client proteins. Specifically, it greatly affected epidermal growth factor receptor (EGFR) signaling cascades by markedly decreasing the levels of total EGFR and EGFR on cell membranes. EGFR knockdown also induced cell-cycle arrest and apoptosis accompanied with a decrease of several EGFR downstream proteins. These results strongly support that EGFR signaling greatly contributes to the ganetespib inhibitory effects. Besides, we found that the responses of GC cell lines to ganetespib correlated well with their EGFR expression levels: MGC-803, as well as AGS and BGC-803, with higher EGFR expression responded to ganetespib better, whereas SGC-7901 and MKN-28 with lower EGFR levels were much less sensitive to ganetespib. Although SGC-7901 and MKN-28 were not very sensitive to ganetespib, ganetespib worked synergistically with radiation and cisplatin in killing them. Importantly, ganetespib significantly inhibited the growth of xenograft tumors in vivo as a single agent or in combination with cisplatin. Results of hematoxylin/eosin staining, TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labeling) assays, and immunohistochemistry staining of phosphorylated cyclin-dependent kinase 1 (pCDK1), EGFR and Ki-67 revealed significant differences in ganetespib-treated tumors. Collectively, our data suggest that ganetespib, as a new potent treatment option, can be used for the molecularly targeted therapy of GC patients according to their expression profiles of EGFR.
Highlights
Identification of key regulatory molecules in Gastric cancer (GC) is of high priority for understanding the mechanism for tumor dissemination as well as the development of novel interventions
Ganetespib treatment resulted in a dose-dependent inhibition of cell viabilities in GC cell lines
First-generation heat-shock protein 90 (HSP90) inhibitors have limited clinical uses because of their toxicity and issues related to solubility and formulation,[32,33] these inhibitors have shown promising anticancer activities and stimulated the discovery of the newgeneration HSP90 inhibitors.[34,35]
Summary
Identification of key regulatory molecules in GC is of high priority for understanding the mechanism for tumor dissemination as well as the development of novel interventions. As an ATP-dependent molecular chaperone protein, HSP90 conducts the proper folding of myriad proteins.[12,14] Abnormally high expression of HSP90 has been found in GC and been greatly considered as an independent prognostic marker of GC progression.[16,17,18] HSP90 remains an attractive therapeutic target in a variety of cancers,[19,20,21,22] and inhibition of HSP90 showed potent growth inhibitory effects on GC in cell cultures and in mouse models.[23,24,25] Ganetespib is a promising second-generation HSP90 inhibitor that does not suffer from the toxicity issues associated with earlier-generation HSP90 inhibitors and exhibits increased potency compared with first- and other second-generation agents.[11,26,27,28,29] In this current study, using cell culture and xenograft mouse models, we sought to evaluate the effects of ganetespib treatments on GC cells, individually or in combination with other treatments. Our results suggested that, as a promising drug candidate, ganetespib has potent antitumor activities on GC, and it is worth being investigated further clinically for the molecularly targeted therapy of GC patients
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