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

doi:10.1038/srep18949

BRAF^V600E 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

Research output: Contribution to journal › Article › peer-review

30 Citations (Scopus)

Abstract

Although BRAF^V600E mutation is associated with adverse clinical outcomes in patients with colorectal cancer (CRC), response and resistance mechanisms for therapeutic BRAF^V600E inhibitors remains poorly understood. In the present study, we demonstrate that selective BRAF^V600E 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 BRAF^V600E inhibition, and AMPK was negatively correlated with BRAF^V600E -dependent activation of MEK-ERK-RSK signaling and positively correlated with unc-51-like kinase 1 (ULK1), a key initiator of autophagy. Furthermore, selective BRAF^V600E 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 BRAF^V600E CRC cells by selective inhibition and suggest that the control of autophagy contributes to overcome the chemoresistance of BRAF^V600E CRC cells.

Original language	English
Article number	18949
Journal	Scientific reports
Volume	6
DOIs	https://doi.org/10.1038/srep18949
Publication status	Published - Jan 11 2016
Externally published	Yes

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10.1038/srep18949

Cite this

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). BRAF^V600E inhibition stimulates AMP-activated protein kinase-mediated autophagy in colorectal cancer cells. Scientific reports, 6, [18949]. https://doi.org/10.1038/srep18949

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, 'BRAF^V600E inhibition stimulates AMP-activated protein kinase-mediated autophagy in colorectal cancer cells', Scientific reports, vol. 6, 18949. https://doi.org/10.1038/srep18949

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title = "BRAFV600E inhibition stimulates AMP-activated protein kinase-mediated autophagy in colorectal cancer cells",

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.",

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

note = "Funding Information: We thank the members of our laboratories for their helpful discussions. In particular, we thank H. Yoshimori, M. Hamasaki, and the members of The Yoshimori Lab of the Department of Genetics, Osaka University Graduate school of Medicine. This work was partly supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology; P-DIRECT; Ministry of Health, Labour and Welfare. Partial support was received as institutional endowments from Taiho Pharmaceutical Co., Ltd., the Evidence Based Medical (EBM) Research Center, Chugai Co., Ltd., and Yakult Honsha Co., Ltd. No funding bodies were involved in data collection or analysis, the decision to publish, or preparation of the manuscript.",

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doi = "10.1038/srep18949",

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AU - Sueda, Toshinori

AU - Sakai, Daisuke

AU - Kawamoto, Koichi

AU - Konno, Masamitsu

AU - Nishida, Naohiro

AU - Koseki, Jun

AU - Colvin, Hugh

AU - Takahashi, Hidekazu

AU - Haraguchi, Naotsugu

AU - Nishimura, Junichi

AU - Hata, Taishi

AU - Takemasa, Ichiro

AU - Mizushima, Tsunekazu

AU - Yamamoto, Hirofumi

AU - Satoh, Taroh

AU - Doki, Yuichiro

AU - Mori, Masaki

AU - Ishii, Hideshi

N1 - Funding Information: We thank the members of our laboratories for their helpful discussions. In particular, we thank H. Yoshimori, M. Hamasaki, and the members of The Yoshimori Lab of the Department of Genetics, Osaka University Graduate school of Medicine. This work was partly supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology; P-DIRECT; Ministry of Health, Labour and Welfare. Partial support was received as institutional endowments from Taiho Pharmaceutical Co., Ltd., the Evidence Based Medical (EBM) Research Center, Chugai Co., Ltd., and Yakult Honsha Co., Ltd. No funding bodies were involved in data collection or analysis, the decision to publish, or preparation of the manuscript.

PY - 2016/1/11

Y1 - 2016/1/11

N2 - 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.

AB - 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.

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