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Targeting Pro-Survival Autophagy Enhanced GSK-3β Inhibition-Induced Apoptosis and Retarded Proliferation in Bladder

Yuko Shirono1, Vladimir Bilim1,2, Tsutomu Anraku1

  • 1Department of Urology, Division of Molecular Oncology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan.

Current Oncology (Toronto, Ont.)
|June 27, 2023
PubMed

Insights

Targeting GSK-3β combined with autophagy inhibitors shows promise for treating advanced bladder cancer (BC). This combination overcomes drug resistance, reducing BC cell growth and promoting apoptosis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Advanced bladder cancer (BC) remains incurable with current treatments.
  • Autophagy induction is a key mechanism of resistance to anticancer therapies.
  • Glycogen synthase kinase 3 beta (GSK-3β) is a potential therapeutic target in BC.

Purpose of the Study:

  • To investigate the synergistic effects of targeting GSK-3β in combination with autophagy inhibitors.
  • To explore mechanisms of secondary resistance to GSK-3β inhibition in BC.
  • To evaluate the potential of this combination therapy to overcome drug resistance.

Main Methods:

  • Utilized small molecule GSK-3β inhibitors and GSK-3β knockdown via siRNA.
  • Assessed the expression of autophagy-related proteins.
  • Investigated the translocation of transcription factor EB (TFEB).
  • Evaluated the effects of combination therapy on BC cell growth and apoptosis.

Main Results:

  • GSK-3β inhibition, alone or via knockdown, increased autophagy-related protein expression.
  • GSK-3β inhibition led to the nucleus translocation of TFEB.
  • Combination of GSK-3β inhibition with chloroquine (autophagy inhibitor) significantly reduced BC cell growth compared to GSK-3β inhibition alone.

Conclusions:

  • Targeting autophagy potentiates GSK-3β inhibition-induced apoptosis in BC cells.
  • Combination therapy retards BC cell proliferation by modulating autophagy.
  • This strategy offers a novel approach to overcome resistance in advanced bladder cancer treatment.
Keywords:
AMPKGSK-3βLC3BTFEBULK1autophagybladder cancer

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