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J Cell Biochem. 2019 Apr;120(4):5315-5325. doi: 10.1002/jcb.27808. Epub 2018 Oct 15.

Signal transducer and activator of transcription 3 inhibition enhances vemurafenib sensitivity in colon cancers harboring the BRAFV600E mutation.

Wang K1, Li Y1, Song N2,3, Che X2,3, Hou K2,3, Xu L2,3, Bai M2,3, Wang Q1, Wang Y1, Zhou Y1, Cao M1, Liu Y2,3, Zhang J1.

Author information

1
Department of Medical Oncology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, China.
2
Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China.
3
Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, China.

Abstract

The BRAFV600E inhibitor vemurafenib is widely used to treat melanomas harboring the activated BRAFV600E 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 BRAFV600E mutant colon cancer cells. When vemurafenib was applied to two colon cancer cell lines with the BRAFV600E 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 BRAFV600E mutant colon cancers.

KEYWORDS:

apoptosis; colon cancer; proliferation; signal transducer and activator of transcription 3; vemurafenib

PMID:
30320916
DOI:
10.1002/jcb.27808

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