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ADAM9 mediates Cisplatin resistance in gastric cancer cells through DNA damage response pathway

Xiao-Yu Zhang1,2, Chan-Yuan Zhao1, Jia-Ming Dong1

  • 1Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.

Medical Oncology (Northwood, London, England)
|March 20, 2025
PubMed

Insights

High ADAM9 expression in gastric cancer promotes chemotherapy resistance by enhancing DNA repair via the ATM-CHK2 pathway, suggesting ADAM9 as a potential therapeutic target to overcome cisplatin resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Gastric cancer is a prevalent malignancy globally, with chemotherapy resistance significantly impacting patient outcomes.
  • Chemotherapy resistance is often linked to enhanced DNA repair mechanisms within tumor cells.
  • ADAM9 (a disintegrin and metalloproteinase domain-9) is implicated in various cancer processes, including drug resistance.

Purpose of the Study:

  • To investigate the role of ADAM9 in cisplatin resistance in gastric cancer.
  • To elucidate the underlying molecular mechanisms of ADAM9-mediated chemotherapy resistance.

Main Methods:

  • Analysis of ADAM9 expression in gastric cancer tissues and its correlation with clinicopathological factors and prognosis.
  • Assessment of cisplatin sensitivity, DNA damage, and expression of DNA damage repair proteins (ATM, CHK2, γ-H2AX) in gastric cancer cells with varying ADAM9 expression levels.
  • Selective interference with ADAM9 expression in gastric cancer cells to evaluate its impact on cisplatin resistance.

Main Results:

  • High ADAM9 expression in gastric cancer tissues correlated with adverse clinicopathological factors and poor prognosis.
  • Elevated ADAM9 expression reduced cisplatin sensitivity, decreased DNA damage, and increased expression of ATM and CHK2.
  • Interference with ADAM9 expression enhanced cisplatin sensitivity, increased DNA damage (indicated by γ-H2AX), and decreased ATM/CHK2 levels.

Conclusions:

  • ADAM9 plays a crucial role in mediating cisplatin resistance in gastric cancer.
  • The mechanism involves the activation of the ATM-CHK2 DNA damage repair pathway.
  • ADAM9 represents a potential therapeutic target for overcoming chemotherapy resistance in gastric cancer.
Keywords:
ADAM9AGSCisplatinDNA damage repairDrug resistanceGastric cancer

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