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Sunitinib induces cellular senescence via p53/Dec1 activation in renal cell carcinoma cells

Yu Zhu1, Le Xu, Jianping Zhang

  • 1Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.

Cancer Science
|April 13, 2013
PubMed

Insights

Sunitinib treatment for metastatic renal cell carcinoma (mRCC) induces cellular senescence, a key mechanism involving p53/Dec1 activation and Raf-1/NF-κB inhibition, leading to tumor growth inhibition and improved survival.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cellular Biology

Background:

  • Sunitinib is a first-line therapy for metastatic renal cell carcinoma (mRCC).
  • The precise molecular mechanisms underlying sunitinib's therapeutic efficacy in mRCC remain unclear.
  • Understanding these mechanisms is crucial for optimizing cancer treatment strategies.

Purpose of the Study:

  • To elucidate the molecular mechanisms of sunitinib's therapeutic effect in renal cell carcinoma (RCC).
  • To investigate the role of cellular senescence in sunitinib's anti-cancer activity.
  • To explore the signaling pathways involved in sunitinib-induced senescence.

Main Methods:

  • In vitro studies using RCC cell lines treated with sunitinib.
  • Analysis of senescence markers (SA-β-gal activity, Dec1, DcR2 expression).
  • Assessment of cell cycle arrest, DNA damage response, and cytokine secretion (SASP).
  • In vivo studies in mouse models and immunohistochemistry on patient tumor tissues.

Main Results:

  • Sunitinib treatment induced cellular senescence, G1-S cell cycle arrest, and DNA damage in RCC cells.
  • Therapy-induced senescence (TIS) was linked to p53/Dec1 signaling activation via Raf-1/NF-κB inhibition.
  • In vivo and patient data showed tumor growth inhibition and prolonged survival correlated with TIS markers.

Conclusions:

  • Sunitinib's therapeutic performance in mRCC is significantly attributed to inducing TIS.
  • The mechanism involves p53/Dec1 activation through the inhibition of Raf-1/NF-κB signaling.
  • Findings suggest potential for enhancing sunitinib efficacy by targeting TIS pathways and managing SASP-related resistance.

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