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Gentisic acid prevents colorectal cancer metastasis via blocking GPR81-mediated DEPDC5 degradation

Guize Feng1, Lijie Zhang2, Weilian Bao3

  • 1Department of Pharmacology & the Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China.

Phytomedicine : International Journal of Phytotherapy and Phytopharmacology
|April 14, 2024
PubMed
Abstract

Insights

Gentisic acid (GA) inhibits colorectal cancer (CRC) metastasis by targeting GPR81 signaling and blocking chaperone-mediated autophagy (CMA). This study reveals GA as a potential therapeutic for CRC metastasis by impeding DEPDC5 degradation.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Colorectal cancer (CRC) metastasis, driven by epithelial-mesenchymal transition (EMT), significantly worsens patient prognosis.
  • G protein-coupled receptor 81 (GPR81) signaling is implicated in tumor metastasis, yet effective specific inhibitors are lacking.
  • Developing novel therapeutic strategies targeting CRC metastasis is crucial.

Purpose of the Study:

  • To investigate the therapeutic effects of Gentisic acid (GA) on colorectal cancer (CRC) metastasis.
  • To elucidate the underlying molecular mechanisms of GA's action in CRC metastasis.
  • To evaluate GA as a potential inhibitor of GPR81 signaling in CRC.

Main Methods:

  • Established mouse models for lung metastasis and subcutaneous tumors, administering GA via intraperitoneal injection.
  • Utilized in vitro models with HCT116 cells treated with lactate to mimic CRC microenvironment.
  • Assessed therapeutic efficacy through survival rates, histopathology, RT-qPCR, and live imaging; explored mechanisms using siRNA, Western blotting, and immunofluorescence.

Main Results:

  • Gentisic acid demonstrated a dose-dependent therapeutic effect on CRC metastasis, improving survival and pathological outcomes.
  • GA functions as a GPR81 inhibitor, suppressing lactate-induced epithelial-mesenchymal transition (EMT) and mTOR signaling in CRC cells both in vivo and in vitro.
  • GA inhibits lactate-induced DEPDC5 degradation by impeding Chaperone-mediated autophagy (CMA) activation.

Conclusions:

  • Chaperone-mediated autophagy (CMA)-dependent DEPDC5 degradation is a critical pathway in lactate/GPR81-mediated CRC metastasis.
  • Gentisic acid shows promise as a therapeutic agent for inhibiting CRC metastasis by targeting GPR81 signaling.
  • Further research into GA's mechanism could lead to novel anti-metastatic therapies for colorectal cancer.
Keywords:
CMADEPDC5EMTGentisic acidmTOR

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