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Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
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Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death

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PCNA and GSK3β interact with each other to regulate H1299 lung adenocarcinoma cells apoptosis

X H Liu1, D E Tang2, Y Dai2

  • 1Key Laboratory of Functional Protein Research of Guangdong Higher Education Institute, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, China.

Neoplasma
|October 15, 2019
PubMed

Insights

Lithium chloride (LiCl) targets glycogen synthase kinase beta (GSK3β) for lung cancer treatment. This study reveals GSK3β interacts with proliferating cell nuclear antigen (PCNA), influencing apoptosis and LiCl sensitivity.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cellular Signaling

Background:

  • Glycogen synthase kinase beta (GSK3β) is a key target for lung cancer therapy, with its inhibitor lithium chloride (LiCl) showing anti-proliferative and apoptosis-modulating effects.
  • Proliferating cell nuclear antigen (PCNA) is crucial for DNA replication and repair, and its role in apoptosis regulation is significant.

Purpose of the Study:

  • To elucidate the interaction between GSK3β and PCNA in lung adenocarcinoma cells.
  • To investigate the regulatory mechanism of GSK3β by PCNA, particularly in response to DNA damage.
  • To determine the functional consequence of the GSK3β-PCNA interaction on lung cancer cell apoptosis and response to LiCl treatment.

Main Methods:

  • GST pull-down and co-immunoprecipitation assays to confirm GSK3β-PCNA interaction in H1299 cells.
  • UVC irradiation to study the dynamic changes in GSK3β-PCNA interaction.
  • Western blotting to assess GSK3β Ser9 phosphorylation levels following PCNA manipulation (overexpression and siRNA knockdown).
  • Pharmacological inhibition of phosphatidylinositol 3-kinase (PI3K) using LY294002 to probe pathway involvement.
  • Functional assays to evaluate the effect of PCNA downregulation on LiCl-induced apoptosis.

Main Results:

  • GSK3β was found to interact with PCNA in H1299 lung adenocarcinoma cells.
  • The GSK3β-PCNA interaction intensity peaked within 3 hours post-UVC irradiation and subsequently decreased.
  • PCNA overexpression reduced GSK3β Ser9 phosphorylation, while PCNA knockdown increased it, an effect reversed by LY294002, implicating the PI3K-AKT pathway.
  • Downregulation of PCNA enhanced the sensitivity of H1299 cells to LiCl-induced apoptosis.

Conclusions:

  • A novel regulatory interaction between GSK3β and PCNA has been identified in lung adenocarcinoma.
  • The PI3K-AKT pathway plays a role in modulating GSK3β phosphorylation in response to PCNA levels and DNA damage.
  • Targeting the PCNA-GSK3β axis presents a promising therapeutic strategy for lung cancer, potentially enhancing LiCl efficacy.

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