Paradoxical action of PP2A inhibition and its potential for therapeutic sensitization

J Cell Physiol. 2024 Nov;239(11):e31413. doi: 10.1002/jcp.31413. Epub 2024 Aug 16.

Abstract

The protein phosphatase 2A (PP2A), a serine/threonine phosphatase, is recognized as a tumor suppressor involved in diverse cellular processes and essential for maintaining cell viability in vivo. However, endogenous inhibitors of PP2A such as cancerous inhibitor of PP2A (CIP2A) and endogenous nuclear protein inhibitor 2 of PP2A (SET) counteract the anticancer function of PP2A, promoting tumorigenesis, development, and drug resistance in tumors. Surprisingly though, contrary to conventional understanding, inhibition of the tumor suppressor gene PP2A with exogenous small molecule compounds can enhance the efficacy of cancer treatment and achieve superior tumor inhibition. Moreover, exogenous PP2A inhibitors resensitize cancers to treatment and provide novel therapeutic strategies for drug-resistant tumors, which warrant further investigation.

Keywords: DNA damage; PP2A inhibition; cell cycle modulation; cellular signal transduction; drug resistance; oncotherapy sensitization.

Publication types

  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Autoantigens
  • DNA-Binding Proteins
  • Drug Resistance, Neoplasm / drug effects
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use
  • Histone Chaperones / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Membrane Proteins
  • Neoplasms* / drug therapy
  • Neoplasms* / genetics
  • Neoplasms* / pathology
  • Protein Phosphatase 2* / antagonists & inhibitors
  • Protein Phosphatase 2* / metabolism

Substances

  • Protein Phosphatase 2
  • Histone Chaperones
  • Antineoplastic Agents
  • SET protein, human
  • Intracellular Signaling Peptides and Proteins
  • Enzyme Inhibitors
  • CIP2A protein, human
  • Autoantigens
  • DNA-Binding Proteins
  • Membrane Proteins