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Topoisomerase inhibitors promote cancer cell motility via ROS-mediated activation of JAK2-STAT1-CXCL1 pathway

Jiafei Liu1, Like Qu1, Lin Meng1

  • 1Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Beijing, 100142, China.

Journal of Experimental & Clinical Cancer Research : CR
|August 24, 2019
PubMed
Abstract

Insights

Topoisomerase inhibitors (TI) promote cancer cell migration and invasion by increasing CXCL1 expression. This process involves reactive oxygen species (ROS), Protein Tyrosine Phosphatase 1B (PTP1B) inactivation, and JAK2-STAT1 pathway activation.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Topoisomerase inhibitors (TI) are used in chemotherapy for their anti-proliferative effects.
  • The impact of TI on cancer cell metastasis remains largely unknown.

Purpose of the Study:

  • To investigate the effects of TI on cancer cell migration and invasion.
  • To elucidate the molecular mechanisms underlying TI-induced cancer cell motility.

Main Methods:

  • Transwell chamber assays were used to assess cancer cell migration and invasion.
  • Mass spectrometry was employed to analyze conditioned medium from TI-treated cells.
  • Gene silencing, neutralizing antibodies, and chemical inhibitors were utilized to validate signaling pathways.

Main Results:

  • TI were found to enhance the migration and invasion of certain cancer cells, dependent on CXCL1.
  • TI treatment increased Janus kinase 2 (JAK2) and Signal transducers and activators of transcription 1 (STAT1) phosphorylation.
  • Reactive oxygen species (ROS) elevation and Protein Tyrosine Phosphatase 1B (PTP1B) oxidation were observed, while glutathione (GSH) reversed these effects.

Conclusions:

  • TI promote cancer cell motility by upregulating CXCL1 expression and secretion.
  • This promotion is mediated by increased ROS, inactivated PTP1B, and activated JAK2-STAT1 signaling.
  • These findings reveal a novel mechanism by which TI can influence cancer metastasis.
Keywords:
CXCL1JAK2-STAT1MotilityPTP1BReactive oxygen speciesTopoisomerase inhibitors

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