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DPP9 regulates NQO1 and ROS to promote resistance to chemotherapy in liver cancer cells

Yunjiang Zhou1, Yaxin Chen1, Chenyuan Xuan1

  • 1State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.

Redox Biology
|August 2, 2024
PubMed

Insights

Dipeptidyl peptidase 9 (DPP9) promotes liver cancer chemoresistance by up-regulating NQO1 and reducing oxidative stress. Inhibiting DPP9/NQO1 signaling may offer a new therapeutic strategy for liver cancer patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Chemotherapy is standard for liver cancer, but drug resistance limits efficacy.
  • Molecular mechanisms of liver cancer chemoresistance are not fully understood.
  • Dipeptidyl peptidase 9 (DPP9) is overexpressed in liver cancer, but its role in chemoresistance is unknown.

Purpose of the Study:

  • To investigate the role of Dipeptidyl peptidase 9 (DPP9) in liver cancer chemoresistance.
  • To elucidate the molecular mechanisms by which DPP9 influences chemoresistance.
  • To evaluate the therapeutic potential of targeting the DPP9/NQO1 pathway.

Main Methods:

  • Assessed DPP9 expression in liver cancer.
  • Investigated DPP9's effect on chemotherapy drug response in liver cancer cells.
  • Analyzed the molecular mechanism involving NRF2, KEAP1, and NQO1.
  • Utilized NQO1 inhibitor (dicoumarol) to assess combination therapy efficacy.

Main Results:

  • DPP9 overexpression was found in liver cancer.
  • DPP9 significantly weakened liver cancer cell response to chemotherapy drugs.
  • DPP9 up-regulates NQO1 and inhibits intracellular reactive oxygen species (ROS) by stabilizing NRF2 protein via KEAP1 binding.
  • Inhibition of NQO1 enhanced chemotherapy efficacy.

Conclusions:

  • DPP9 promotes liver cancer chemoresistance by up-regulating NQO1 and reducing ROS levels.
  • The DPP9/NRF2/NQO1 pathway is a key mechanism in liver cancer chemoresistance.
  • Inhibiting DPP9/NQO1 signaling presents a promising therapeutic strategy for overcoming liver cancer chemoresistance.
Keywords:
DPP9Drug resistanceLiver cancerNQO1ROS

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