2. Academic Validation
  3. Larotrectinib induces autophagic cell death through AMPK/mTOR signalling in colon cancer

Larotrectinib induces autophagic cell death through AMPK/mTOR signalling in colon cancer

  • J Cell Mol Med. 2022 Oct 17. doi: 10.1111/jcmm.17530.
Wencheng Kong 1 2,  Hangzhang Zhu 2,  Sixing Zheng 2,  Guang Yin 2,  Panpan Yu 2,  Yuqiang Shan 2,  Xinchun Liu 2,  Rongchao Ying 2,  Hong Zhu 1,  Shenglin Ma 3
Affiliations

Affiliations

  • 1 Zhejiang Province Key Laboratory of Anti-cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
  • 2 Department of Gastroenterological Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 3 Translational Medicine Research Center, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
PMID: 36251949 DOI: 10.1111/jcmm.17530
Abstract

Larotrectinib (Lar) is a highly selective and potent small-molecule inhibitor used in patients with tropomyosin receptor kinase (Trk) fusion-positive cancers, including colon Cancer. However, the underlying molecular mechanisms specifically in patients with colon Cancer have not yet been explored. Our data showed that Lar significantly suppressed proliferation and migration of colon Cancer cells. In addition, Lar suppressed the epithelial-mesenchymal transition (EMT) process, as evidenced by elevation in E-cadherin (E-cad), and downregulation of vimentin and matrix metalloproteinase (MMP) 2/9 expression. Furthermore, Lar was found to activate autophagic flux, in which Lar increased the ratio between LC3II/LC3I and decreased the expression of p62 in colon Cancer cells. More importantly, Lar also increased AMPK phosphorylation and suppressed mTOR phosphorylation in colon Cancer cells. However, when we silenced AMPK in colon Cancer cells, Lar-induced accumulation of autolysomes as well as Lar-induced suppression of the EMT process were significantly diminished. An in vivo assay also confirmed that tumour volume and weight decreased in Lar-treated mice than in control mice. Taken together, this study suggests that Lar significantly suppresses colon Cancer proliferation and migration by activating AMPK/mTOR-mediated autophagic cell death.

Keywords

AMPK/mTOR signalling; Larotrectinib; autophagy flux; colon cancer; epithelial-mesenchymal transition.

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