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PTEN-deficient, chromosomal instability colorectal cancer is hypersensitive to STAT3 inhibition

Guowen Ren1,2, Yue Pu1, Xiumei Zhang1

  • 1Cancer Centre, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China.

International Journal of Biological Sciences
|November 25, 2025
PubMed

Insights

Targeting STAT3 in PTEN-deficient colorectal cancer (CRC) offers a new therapy. Inhibiting STAT3 causes cell death in CRC by disrupting mitosis and spindle formation.

Area of Science:

  • Oncology
  • Cell Biology
  • Genetics

Background:

  • Chromosomal instability (CIN) in colorectal cancer (CRC) presents therapeutic targets.
  • PTEN deficiency is common in CRC and linked to CIN.
  • Understanding vulnerabilities in PTEN-deficient CRC is crucial for treatment development.

Purpose of the Study:

  • To identify therapeutic vulnerabilities in PTEN-deficient colorectal cancer (CRC) cells.
  • To investigate the role of STAT3 inhibition in PTEN-deficient CRC.
  • To elucidate the molecular mechanisms underlying STAT3 inhibition's effect on CRC cells.

Main Methods:

  • Utilized PTEN-deficient CRC cell models.
  • Assessed sensitivity to STAT3 inhibition.
  • Analyzed STAT3 and PLK1 phosphorylation.
  • Investigated spindle formation and mitotic progression.
  • Examined STMN1 dependency.

Main Results:

  • PTEN-deficient CRC cells showed increased CIN and hypersensitivity to STAT3 inhibition.
  • STAT3 inhibition led to abnormal spindle formation, mitotic arrest, and cell death.
  • PTEN deficiency increased STAT3 phosphorylation and PLK1 hyperactivation, causing abnormal spindles and CIN.
  • STAT3 inhibition suppressed PLK1 phosphorylation via STMN1, enhancing mitotic defects.

Conclusions:

  • Targeting the STAT3-PLK1 axis is a potential therapeutic strategy for PTEN-loss colorectal cancer.
  • STAT3 inhibition effectively induces mitotic catastrophe in PTEN-deficient CRC.
  • The STMN1-dependent suppression of PLK1 phosphorylation is key to STAT3 inhibition's efficacy.
Keywords:
Colorectal cancerPLK1PTENSTAT3Synthetic lethalitychromosomal instability

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