Journal
CANCER LETTERS
Volume 356, Issue 2, Pages 828-836Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2014.10.034
Keywords
SAHA; MET; XL184; Combination therapy
Categories
Funding
- National Natural Science Foundation of China [8137340]
- Zhejiang Provincial Natural Science Foundation [LY14H310008]
- Zhejiang Province Joint Construction Project [WKJ-ZJ-10]
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Although SAHA is approved for the treatment of cutaneous T-cell lymphoma by the U.S. Food and Drug Administration, clinical trials using SAHA as a monotherapy or in combination with other chemotherapeutic agents in solid tumors have not met with success, and the mechanisms of tolerance remain unknown. In this study, using the prostate cancer cell line PC3 and the non-small lung cancer cell line A549, which have limited sensitivity to SAHA, we found that SAHA triggered MET and AKT phosphorylation at clinical concentrations. siRNA silencing of MET enhanced SAHA induced apoptosis in PD and A549 cells. However, MET protein expression and HGF secretion were not affected by SAHA, suggesting that the SAHA-induced MET activation was not due to MET over-expression or HGF paracrine secretion. However, mRNA and protein expression of the laminin receptor integrin alpha 5 beta 1 was up-regulated by SAHA prior to MET activation. Silencing of integrin alpha 5 beta 1 abolished SAHA-triggered MET phosphorylation, suggesting the involvement of integrin alpha 5 beta 1 in MET activation. Further, the combination of SAHA and XL184 resulted in a synergistic induction of cancer cell apoptosis and a synergistic inhibition of tumor growth. These data indicate that SAHA triggered MET activation in an HGF independent manner. This effect is partially involved in the resistance to SAHA in solid cancers, warranting further clinical investigation into combining SAHA with MET inhibitors in solid cancer treatment. (C) 2014 Elsevier Ireland Ltd. All rights reserved.
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