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Topotecan induces apoptosis via ASCT2 mediated oxidative stress in gastric cancer

Lai Wang1, Yang Liu2, Ting-Li Zhao1

  • 1Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, China.

Phytomedicine : International Journal of Phytotherapy and Phytopharmacology
|January 23, 2019
PubMed
Abstract

Insights

Topotecan (TPT) reduces gastric cancer growth by inhibiting glutamine uptake via ASCT2, increasing oxidative stress, and inducing apoptosis. ASCT2 is a potential anti-cancer target for TPT therapy.

Area of Science:

  • Oncology
  • Cancer Metabolism
  • Molecular Biology

Background:

  • Topotecan (TPT), a Topoisomerase I inhibitor, demonstrates anti-cancer effects in gastric cancer.
  • Cancer cells exhibit metabolic reprogramming for increased nutrient uptake, a known hallmark of cancer.
  • The impact of TPT on gastric cancer metabolism remains largely unexplored.

Purpose of the Study:

  • To elucidate the effects of Topotecan (TPT) on metabolic pathways in gastric cancer.
  • To investigate the role of ASCT2 in TPT-mediated gastric cancer cell growth inhibition.

Main Methods:

  • Assessed ATP production, glucose, and glutamine uptake using assay kits.
  • Quantified glutathione (GSH) and reactive oxygen species (ROS) levels.
  • Determined apoptosis rates, mitochondrial membrane potential (MMP), and protein expression via flow cytometry and western blotting.

Main Results:

  • TPT treatment increased ATP production and glucose uptake (via HK2/GLUT1 upregulation) but decreased glutamine uptake (via ASCT2 downregulation).
  • ASCT2 inhibition or knockdown significantly suppressed gastric cancer cell growth, reduced GSH, and increased ROS.
  • ASCT2 knockdown induced apoptosis through the mitochondrial pathway and diminished TPT's anti-cancer efficacy.

Conclusions:

  • TPT inhibits gastric cancer proliferation by downregulating ASCT2, leading to oxidative stress and apoptosis via the mitochondrial pathway.
  • ASCT2 plays a crucial role in regulating gastric cancer cell proliferation.
  • ASCT2 represents a promising therapeutic target for Topotecan (TPT) in gastric cancer treatment.
Keywords:
ASCT2ApoptosisGastric cancerOxidative stressTopotecan

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