1. Academic Validation
  2. PROX1 induction by autolysosomal activity stabilizes persister-like state of colon cancer via feedback repression of the NOX1-mTORC1 pathway

PROX1 induction by autolysosomal activity stabilizes persister-like state of colon cancer via feedback repression of the NOX1-mTORC1 pathway

  • Cell Rep. 2023 May 17;112519. doi: 10.1016/j.celrep.2023.112519.
Hirokazu Ohata 1 Daisuke Shiokawa 2 Hiroaki Sakai 1 Yusuke Kanda 1 Yoshie Okimoto 1 Syuzo Kaneko 3 Ryuji Hamamoto 3 Hitoshi Nakagama 4 Koji Okamoto 5
Affiliations

Affiliations

  • 1 Teikyo University, Advanced Comprehensive Research Organization, Tokyo 173-0003, Japan.
  • 2 Division of Molecular Pharmacology, Tokyo 104-0045, Japan.
  • 3 Division of Medical AI Research and Development, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
  • 4 National Cancer Center, Tokyo 104-0045, Japan.
  • 5 Teikyo University, Advanced Comprehensive Research Organization, Tokyo 173-0003, Japan. Electronic address: okamoto.kouji.dm@teikyo-u.ac.jp.
Abstract

Cancer chemoresistance is often attributed to slow-cycling persister populations with Cancer stem cell (CSC)-like features. However, how persister populations emerge and prevail in Cancer remains obscure. We previously demonstrated that while the NOX1-mTORC1 pathway is responsible for proliferation of a fast-cycling CSC population, PROX1 expression is required for chemoresistant persisters in colon Cancer. Here, we show that enhanced autolysosomal activity mediated by mTORC1 inhibition induces PROX1 expression and that PROX1 induction in turn inhibits NOX1-mTORC1 activation. CDX2, identified as a transcriptional activator of NOX1, mediates PROX1-dependent NOX1 inhibition. PROX1-positive and CDX2-positive cells are present in distinct populations, and mTOR inhibition triggers conversion of the CDX2-positive population to the PROX1-positive population. Inhibition of Autophagy synergizes with mTOR inhibition to block Cancer proliferation. Thus, mTORC1 inhibition-mediated induction of PROX1 stabilizes a persister-like state with high autolysosomal activity via a feedback regulation that involves a key cascade of proliferating CSCs.

Keywords

CP: Cancer; NOX1; PROX1; autophagy; colon cancer; mTORC1; persister cells.

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