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Evaluating Autophagy Levels in Two Different Pancreatic Cell Models Using LC3 Immunofluorescence
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Cezanne promoted autophagy through PIK3C3 stabilization and PIK3C2A transcription in lung adenocarcinoma

Yadong Wang1, Jiahao Li1, Haotian Zheng1

  • 1Institute of Oncology, Shandong Provincial Hospital, Shandong University, Jinan, People's Republic of China.

Cell Death Discovery
|August 18, 2023
PubMed

Insights

Cezanne, an autophagy regulator, promotes Osimertinib resistance in lung adenocarcinoma by stabilizing PIK3C3 and upregulating PIK3C2A. Inhibiting autophagy with chloroquine can reverse this resistance, offering new therapeutic strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cellular Biology

Background:

  • Osimertinib is a key treatment for EGFR-mutated lung adenocarcinoma (LUAD).
  • Acquired resistance to Osimertinib limits its long-term effectiveness.
  • Autophagy, a cellular process, plays a significant role in promoting this resistance.

Purpose of the Study:

  • To identify and characterize novel autophagy-regulatory factors contributing to Osimertinib resistance.
  • To elucidate the molecular mechanisms by which these factors mediate resistance in LUAD.

Main Methods:

  • Investigated Cezanne, an OTU-deubiquitinase, as a potential autophagy regulator.
  • Assessed Cezanne expression in Osimertinib-resistant LUAD cells.
  • Utilized autophagy inhibitors (e.g., chloroquine) and inducers (e.g., rapamycin, EBSS).
  • Analyzed protein stabilization (PIK3C3) and gene upregulation (PIK3C2A) via deubiquitination and transcriptional regulation (POLR2A).

Main Results:

  • Cezanne was highly expressed in Osimertinib-resistant cells and promoted resistance.
  • Cezanne overexpression activated autophagy independently of standard inducers.
  • Cezanne stabilized PIK3C3 by removing K48-linked ubiquitination.
  • Cezanne upregulated PIK3C2A transcription, contributing to PI3P generation.
  • Cezanne was found to accelerate EGFR recycling, linking it to Osimertinib resistance.

Conclusions:

  • Cezanne is identified as a novel autophagy regulator that promotes Osimertinib resistance in LUAD.
  • The study establishes a new mechanistic link between Cezanne, autophagy activation, and Osimertinib resistance.
  • Targeting Cezanne or modulating autophagy presents a potential therapeutic strategy to overcome Osimertinib resistance in LUAD.

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