BRAFV600E inhibition stimulates AMP-activated protein kinase-mediated autophagy in colorectal cancer cells

Toshinori Sueda, Daisuke Sakai, Koichi Kawamoto, Masamitsu Konno, Naohiro Nishida, Jun Koseki, Hugh Colvin, Hidekazu Takahashi, Naotsugu Haraguchi, Junichi Nishimura, Taishi Hata, Ichiro Takemasa, Tsunekazu Mizushima, Hirofumi Yamamoto, Taroh Satoh, Yuichiro Doki, Masaki Mori, Hideshi Ishii

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18 Citations (Scopus)

Abstract

Although BRAFV600E mutation is associated with adverse clinical outcomes in patients with colorectal cancer (CRC), response and resistance mechanisms for therapeutic BRAFV600E inhibitors remains poorly understood. In the present study, we demonstrate that selective BRAFV600E inhibition activates AMP-activated protein kinase (AMPK), which induces autophagy as a mechanism of therapeutic resistance in human cancers. The present data show AMPK-dependent cytoprotective roles of autophagy under conditions of therapeutic BRAFV600E inhibition, and AMPK was negatively correlated with BRAFV600E -dependent activation of MEK-ERK-RSK signaling and positively correlated with unc-51-like kinase 1 (ULK1), a key initiator of autophagy. Furthermore, selective BRAFV600E inhibition and concomitant suppression of autophagy led to the induction of apoptosis. Taken together, present experiments indicate that AMPK plays a role in the survival of BRAFV600E CRC cells by selective inhibition and suggest that the control of autophagy contributes to overcome the chemoresistance of BRAFV600E CRC cells.

Original languageEnglish
Article number18949
JournalScientific reports
Volume6
DOIs
Publication statusPublished - Jan 11 2016
Externally publishedYes

All Science Journal Classification (ASJC) codes

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    Sueda, T., Sakai, D., Kawamoto, K., Konno, M., Nishida, N., Koseki, J., Colvin, H., Takahashi, H., Haraguchi, N., Nishimura, J., Hata, T., Takemasa, I., Mizushima, T., Yamamoto, H., Satoh, T., Doki, Y., Mori, M., & Ishii, H. (2016). BRAFV600E inhibition stimulates AMP-activated protein kinase-mediated autophagy in colorectal cancer cells. Scientific reports, 6, [18949]. https://doi.org/10.1038/srep18949