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TIMP-2 regulates 5-Fu resistance via the ERK/MAPK signaling pathway in colorectal cancer

Guolin Zhang1,2, Xin Luo1, Zian Wang1,3

  • 1Department of Colorectal Surgery, Sir Run Run Shaw Hospital of Zhejiang University, Hangzhou, China.

Aging
|January 13, 2022
PubMed

Insights

Tissue inhibitor metalloproteinase 2 (TIMP-2) drives 5-Fluorouracil (5-Fu) resistance in colorectal cancer by activating the ERK/MAPK pathway. Targeting TIMP-2 or ERK/MAPK may overcome this chemotherapy resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • 5-Fluorouracil (5-Fu) is a primary chemotherapy for colorectal cancer (CRC).
  • Drug resistance significantly limits 5-Fu efficacy in CRC patients.
  • The role of cytokines in mediating chemotherapy resistance remains largely unexplored.

Purpose of the Study:

  • To investigate the role of cytokines in 5-Fu resistance in colorectal cancer.
  • To identify novel mechanisms underlying 5-Fu resistance.
  • To explore potential therapeutic targets for overcoming 5-Fu resistance.

Main Methods:

  • Cytokine array analysis to identify differentially expressed cytokines in 5-Fu resistant CRC.
  • Analysis of TIMP-2 expression in patient samples and a patient-derived xenograft (PDX) model.
  • Investigation of the autocrine mechanism involving TIMP-2 and the ERK/MAPK pathway.
  • Inhibition studies using anti-TIMP-2 antibodies and U0126 (ERK/MAPK inhibitor).

Main Results:

  • Tissue inhibitor metalloproteinase 2 (TIMP-2) was highly expressed in 5-Fu resistant CRC patients and PDX models.
  • Elevated TIMP-2 levels correlated with poor prognostic outcomes in 84 CRC patients.
  • TIMP-2 activates the ERK/MAPK signaling pathway, sustaining 5-Fu resistance via an autocrine mechanism.
  • Inhibition of TIMP-2 or ERK/MAPK signaling reversed 5-Fu resistance in CRC models.

Conclusions:

  • A novel TIMP-2-ERK/MAPK mediated mechanism contributes to 5-Fu resistance in colorectal cancer.
  • TIMP-2 is a potential biomarker for predicting 5-Fu resistance and prognosis in CRC.
  • Targeting TIMP-2 or the ERK/MAPK pathway presents a promising strategy to enhance 5-Fu chemotherapy efficacy in CRC.
Keywords:
5-FuERK/MAPK signaling pathwayTIMP-2colorectal cancerdrug resistance

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