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p53-regulated SESN1 and SESN2 regulate cell proliferation and cell death through control of STAT3

Alexander Haidurov1, Andrei O Zheltukhin2, Anastasiya V Snezhkina2

  • 1School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Pearse Street, Dublin 2, Ireland.

Cell Communication and Signaling : CCS
|February 22, 2025
PubMed

Insights

Sestrin1 and Sestrin2 (SESN1&2) proteins regulate cell growth and viability. Their inactivation promotes cancer by activating STAT3 via PTPRD downregulation, suggesting SESN1&2 reactivation as a cancer therapy.

Area of Science:

  • Cellular biology
  • Molecular oncology
  • Stress response pathways

Background:

  • Sestrin1 and Sestrin2 (SESN1&2) are stress-responsive proteins regulating cell growth and viability.
  • While known to target mTORC1, SESN1&2 also influence cellular processes independently of mTORC1.
  • STAT3 is a transcription factor frequently overactivated in cancers, promoting proliferation and inhibiting apoptosis.

Purpose of the Study:

  • To elucidate a novel, mTORC1-independent mechanism by which SESN1&2 regulate cell proliferation and death.
  • To investigate the role of SESN1&2 in controlling STAT3 activity.
  • To explore the implications of SESN1&2-STAT3 interaction in cancer development and drug resistance.

Main Methods:

  • Utilized lung adenocarcinoma A549 cells to study SESN1&2 function.
  • Assessed the impact of SESN1&2 inactivation on cell proliferation and death.
  • Investigated the regulatory relationship between SESN1&2, STAT3, and the PTPRD phosphatase.

Main Results:

  • SESN1&2 inactivation accelerated cell proliferation and conferred resistance to cell death.
  • This inactivation occurred independently of mTORC1 activity.
  • SESN1&2 deficiency led to STAT3 activation by downregulating the PTPRD phosphatase, which normally dephosphorylates STAT3.

Conclusions:

  • SESN1&2 suppress STAT3 activity through PTPRD-mediated dephosphorylation.
  • SESN1&2 deficiency promotes STAT3 activation, contributing to carcinogenesis and drug resistance.
  • Reactivation of SESN1&2 represents a potential therapeutic strategy for cancer treatment.
Keywords:
Cell deathLung cancerSESN1/2STAT3

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