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Sunitinib promotes apoptosis via p38 MAPK activation and STAT3 downregulation in oral keratinocytes

Shohei Fukada1, Kouji Ohta2, Miyuki Sakuma1

  • 1Department of Oral and Maxillofacial Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.

Oral Diseases
|November 30, 2022
PubMed
Abstract

Insights

Sunitinib causes oral keratinocyte injury and apoptosis through p38 activation and STAT3 downregulation. These cytotoxic effects may explain sunitinib-related oral complications in cancer patients.

Area of Science:

  • Oncology
  • Cell Biology
  • Pharmacology

Background:

  • Sunitinib is a tyrosine kinase inhibitor used for metastatic renal cell carcinoma.
  • Oral mucosal complications like stomatitis are common in patients treated with sunitinib.
  • The cytotoxic effects of sunitinib on oral keratinocytes are not well understood.

Purpose of the Study:

  • To investigate the effects of sunitinib on oral keratinocytes.
  • To elucidate the mechanisms of sunitinib-induced cell injury and apoptosis.
  • To identify the signaling pathways involved in sunitinib's effects on oral keratinocytes.

Main Methods:

  • Sunitinib's effects on immortalized oral keratinocytes (RT7 cells) and primary oral keratinocytes were assessed.
  • Cell injury was measured by lactate dehydrogenase (LDH) release.
  • Apoptosis was evaluated through DNA fragmentation, protein expression (Bcl-2, PARP, caspases), and Western blotting for signaling pathways (MAPK, STAT3).

Main Results:

  • Sunitinib significantly increased LDH release, indicating cell injury.
  • The drug induced apoptosis, evidenced by DNA fragmentation and altered expression of apoptosis-related proteins (Bcl-2, PARP, caspase 3/9).
  • Sunitinib increased p38 MAPK phosphorylation, decreased STAT3 phosphorylation, and these changes were linked to cell injury and apoptosis.

Conclusions:

  • Sunitinib induces cell injury and apoptosis in oral keratinocytes.
  • The mechanism involves p38 MAPK activation and STAT3 downregulation.
  • These findings suggest sunitinib's cytotoxic effects on oral keratinocytes contribute to oral complications during cancer therapy.
Keywords:
STAT3apoptosisoral keratinocytesp38 MAPKsunitinib

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