SAHA triggered MET activation contributes to SAHA tolerance in solid cancer cells
SAHA triggered MET activation contributes to SAHA tolerance in solid cancer cells
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SAHA 触发的 MET 激活有助于实体癌细胞中的 SAHA 耐受
DOI：
10.1016/j.canlet.2014.10.034
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发表时间：
2015-01-28
期刊：
影响因子：
9.7
通讯作者：
Yang, Bo
中科院分区：
文献类型：
--
作者：
Ding, Ling;Zhang, Ziyi;Yang, Bo
尽管SAHA被美国食品和药物管理局批准用于治疗皮肤T细胞淋巴瘤，但将SAHA作为单一疗法或与其他化疗药物联合用于实体肿瘤的临床试验尚未取得成功，耐受机制仍不清楚。在本研究中，使用对SAHA敏感性有限的前列腺癌PC3细胞和非小细胞肺癌细胞A549，我们发现SAHA在临床浓度下触发了MET和AKT的磷酸化。MET的siRNA沉默增强了SAHA诱导PD和A549细胞的凋亡。但SAHA不影响MET蛋白表达和HGF分泌，提示SAHA诱导的MET活化不是由于MET过度表达或HGF旁分泌所致。然而，在MET激活之前，SAHA上调了层粘连蛋白受体整合素α5β1的mRNA和蛋白表达。沉默整合素α5β1可消除SAHA触发的MET磷酸化，提示整合素α5β1参与了MET的激活。此外，SAHA和XL184的结合产生了协同诱导癌细胞凋亡和协同抑制肿瘤生长的作用。这些数据表明SAHA以一种不依赖于HGF的方式触发了MET的激活。这一效应部分与实体肿瘤对SAHA的耐药性有关，值得进一步的临床研究，将SAHA与MET抑制剂联合用于实体肿瘤治疗。(C)2014爱思唯尔爱尔兰有限公司。保留所有权利。
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.