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MGMT expression affects the gemcitabine resistance of pancreatic cancer cells

Yu Shi1, Yan Wang1, Jing Qian1

  • 1Department of Radiotherapy, Affiliated Hospital of Nantong University, Nantong 226001, China.

Life Sciences
|July 30, 2020
PubMed

Insights

O6-methylguanine-DNA methyltransferase (MGMT) inhibition overcomes gemcitabine resistance in pancreatic cancer by suppressing proliferation and promoting apoptosis. PVT1 silencing also enhances gemcitabine efficacy by inhibiting the SHH/GLI pathway.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Pancreatic cancer exhibits poor prognosis and resistance to standard chemotherapy like gemcitabine.
  • The O6-methylguanine-DNA methyltransferase (MGMT) enzyme plays a role in DNA repair and can influence chemotherapy resistance.
  • The SHH/GLI signaling pathway is implicated in various cancers, including pancreatic cancer.

Purpose of the Study:

  • To investigate the role of MGMT in gemcitabine resistance in pancreatic cancer cells.
  • To explore the regulatory mechanism involving the SHH/GLI signaling pathway.
  • To assess the therapeutic potential of MGMT inhibition and PVT1 silencing.

Main Methods:

  • Utilized PanC-1/GEM pancreatic cancer cell lines.
  • Administered lomeguatrib (LM) for MGMT inhibition.
  • Performed PVT1 silencing experiments.
  • Conducted xenograft studies in nude mice treated with gemcitabine.
  • Analyzed protein expression levels (Caspase-3, Bax, Bcl-2, Beclin1, Atg5) and pathway activity (SHH/GLI).

Main Results:

  • MGMT inhibition by LM suppressed proliferation, invasion, migration, and autophagy while promoting apoptosis in PanC-1/GEM cells.
  • MGMT inhibition increased gemcitabine efficacy and modulated apoptosis-related proteins.
  • PVT1 silencing mimicked MGMT inhibition effects and inhibited the SHH/GLI pathway by regulating MGMT.
  • GLI overexpression reversed the effects of PVT1 silencing.
  • In vivo studies confirmed that MGMT inhibition and PVT1 silencing suppressed tumor growth and promoted apoptosis.

Conclusions:

  • MGMT inhibition is a promising strategy to overcome gemcitabine resistance in pancreatic cancer.
  • PVT1 silencing impacts pancreatic cancer progression by modulating MGMT expression and inhibiting the SHH/GLI signaling pathway.
  • Targeting MGMT and the PVT1/SHH/GLI axis offers potential therapeutic avenues for pancreatic cancer treatment.
Keywords:
GemcitabineMGMTPancreatic cancerResistance

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