期刊
JOURNAL OF CELLULAR BIOCHEMISTRY
卷 120, 期 4, 页码 5315-5325出版社
WILEY
DOI: 10.1002/jcb.27808
关键词
apoptosis; colon cancer; proliferation; signal transducer and activator of transcription 3; vemurafenib
资金
- Educational Commission of Liaoning Province of China [20060973]
- Natural Science Foundation of Liaoning Province [20180530092]
- Science and Technology Planning Project of Liaoning Province of China [2011404013-9, 2007225009-1, 2013225079]
- National Natural Science Foundation of China [81372532]
- Science and Technology Planning Project of Shenyang [F15-139-9-27]
The BRAF(V600E) inhibitor vemurafenib is widely used to treat melanomas harboring the activated BRAF(V600E) mutation; however, vemurafenib showed poor efficacy in colon cancer, which impeded its clinical application for colon cancer patients with this mutation. The specific mechanism of vemurafenib resistance is not clear in colon cancer. In this study, we demonstrated that signal transducer and activator of transcription 3 (STAT3) activation influenced vemurafenib sensitivity in BRAF(V600E) mutant colon cancer cells. When vemurafenib was applied to two colon cancer cell lines with the BRAF(V600E) mutation, STAT3 was continuously activated after 6 hours. Furthermore, BCL-2 was upregulated in RKO colon cancer cells, while STAT3 remained unchanged in HT-29 colon cancer cells. This suggested that STAT3 signaling might be involved in vemurafenib sensitivity. Combining the STAT3 inhibitor STATTIC with vemurafenib further inhibited cell proliferation and promoted apoptosis by downregulating STAT3 and BCL-2 expression in RKO cells. Further studies showed that interleukin 6 (IL-6) secretion increased after RKO cells were treated with vemurafenib. STAT3 activation was induced by adding IL-6 to the supernatant, and IL-6 increased STAT3 and BCL-2 expression and antagonized vemurafenib sensitivity in HT-29 cells. Together, these results suggest that STAT3 activation maybe related to vemurafenib sensitivity in colon cancer cells, and that combining STAT3 inhibitors with vemurafenib may be a promising treatment for BRAF(V600E) mutant colon cancers.
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