2. Academic Validation
  3. MCT1 relieves osimertinib-induced CRC suppression by promoting autophagy through the LKB1/AMPK signaling

MCT1 relieves osimertinib-induced CRC suppression by promoting autophagy through the LKB1/AMPK signaling

  • Cell Death Dis. 2019 Aug 13;10(8):615. doi: 10.1038/s41419-019-1844-2.
Ping Jin 1,  Jingwen Jiang 1,  Na Xie 1,  Li Zhou 1,  Zhao Huang 1,  Lu Zhang 1,  Siyuan Qin 1,  Shuyue Fu 1,  Liyuan Peng 1,  Wei Gao 1,  Bowen Li 1,  Yunlong Lei 2,  Edouard C Nice 3,  Changlong Li 4,  Jichun Shao 5,  Ke Xie 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, P. R. China.
  • 2 Department of Biochemistry and Molecular Biology, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, 400016, P. R. China.
  • 3 Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, 3800, Australia.
  • 4 West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, China.
  • 5 Department of Urology, Second Affiliated Hospital of Chengdu Medical College (China National Nuclear Corporation 416 Hospital), Chengdu, Sichuan, China. shaoji93@163.com.
  • 6 Department of Oncology, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610054, P. R. China. xieke@med.uestc.edu.cn.
PMID: 31409796 DOI: 10.1038/s41419-019-1844-2
Abstract

Colorectal Cancer (CRC) is one of the most frequently diagnosed cancers worldwide. Development of novel chemotherapeutics is still required to enable successful treatment and improve survival for CRC patients. Here, we found that osimertinib (OSI) exhibits potent anti-CRC effects by inducing Apoptosis, independent of its selective inhibitory activity targeting the EGFR T790M mutation. Intriguingly, OSI treatment triggers autophagic flux in CRC cells. Inhibition of Autophagy markedly augments OSI-induced Apoptosis and growth inhibition in CRC cells, suggesting a protective role of Autophagy in response to OSI treatment. Mechanistically, OSI upregulates the expression of Monocarboxylate Transporter 1 (MCT1) and subsequently activates LKB1/AMPK signaling, leading to Autophagy induction in CRC cells. Notably, OSI significantly exaggerates the sensitivity of CRC cells to the first-line drugs 5-fluorouracil or oxaliplatin. Taken together, our study unravels a novel mechanism of OSI-mediated protective Autophagy involving MCT1/LKB1/AMPK signaling, and suggests the use of OSI as a potential agent for clinical CRC treatment.

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