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PI3K Promotes Basal Cell Carcinoma Growth Through Kinase-Induced p21 Degradation

Rachel Y Chow1, Ung Seop Jeon1, Taylor M Levee1

  • 1Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA, United States.

Frontiers in Oncology
|July 16, 2021
PubMed

Insights

This study reveals that the PI3K pathway drives basal cell carcinoma (BCC) growth by degrading p21, offering potential new therapeutic targets beyond Hedgehog (HH) pathway inhibitors for advanced BCC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Basal cell carcinoma (BCC) is a common skin cancer driven by the Hedgehog (HH) pathway.
  • Advanced BCCs often develop resistance to Smoothened (SMO) inhibitors, necessitating alternative treatment strategies.
  • Identifying pathways that bypass SMO inhibition is crucial for treating advanced or metastatic BCC.

Purpose of the Study:

  • To identify alternative molecular pathways driving BCC progression.
  • To investigate the role of the PI3K pathway in BCC development and resistance.
  • To explore potential therapeutic targets for advanced BCC.

Main Methods:

  • RNA-sequencing analysis of human BCC tumor-normal pairs.
  • Immunostaining of human and mouse BCC samples.
  • Pharmacological inhibition of PI3K in BCC cell lines and mouse models.

Main Results:

  • A PI3K pathway expression signature was identified in BCC.
  • PI3K inhibition reduced BCC cell proliferation and HH signaling in vitro.
  • PI3K inhibition in mouse BCC models reduced tumor growth but did not affect HH signaling.
  • PI3K inhibition led to decreased active aPKC and Akt1, and increased p21 stability.

Conclusions:

  • PI3K signaling promotes BCC tumor growth through kinase-induced p21 degradation.
  • This mechanism of BCC growth appears to be independent of HH signaling alterations.
  • Targeting the PI3K pathway offers a potential therapeutic strategy for BCC, independent of HH pathway modulation.
Keywords:
PI3K - AKT pathwayatypical PKCιbasal cell carcinomahedgehogp21

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