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

被引：37

作者：

Sueda, Toshinori ^{[1
,2
]}

Sakai, Daisuke ^{[1
]}

Kawamoto, Koichi ^{[2
]}

Konno, Masamitsu ^{[1
]}

Nishida, Naohiro ^{[1
]}

Koseki, Jun ^{[3
]}

Colvin, Hugh ^{[1
,2
,3
]}

Takahashi, Hidekazu ^{[2
]}

Haraguchi, Naotsugu ^{[2
]}

Nishimura, Junichi ^{[2
]}

Hata, Taishi ^{[2
]}

Takemasa, Ichiro ^{[2
]}

Mizushima, Tsunekazu ^{[2
]}

Yamamoto, Hirofumi ^{[4
]}

Satoh, Taroh ^{[1
]}

Doki, Yuichiro ^{[1
,2
,3
]}

Mori, Masaki ^{[1
,2
,3
]}

Ishii, Hideshi ^{[1
,3
]}

机构：

[1] Osaka Univ, Grad Sch Med, Dept Frontier Sci Canc & Chemotherapy, Suita, Osaka 5650871, Japan

[2] Osaka Univ, Grad Sch Med, Dept Gastrointestinal Surg, Suita, Osaka 5650871, Japan

[3] Osaka Univ, Grad Sch Med, Dept Canc Profiling Discovery, Suita, Osaka 5650871, Japan

[4] Osaka Univ, Grad Sch Med & Hlth Sci, Dept Mol Pathol, Suita, Osaka 5650871, Japan

来源：

SCIENTIFIC REPORTS | 2016年 / 6卷

关键词：

ENERGY SENSOR; BRAF; PHOSPHORYLATION; RESISTANCE; PATHWAY; NUTRIENT; GROWTH; TARGET; LKB1;

D O I：

10.1038/srep18949

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：14

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