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Chk1 targeting reactivates PP2A tumor suppressor activity in cancer cells

Anchit Khanna1, Otto Kauko, Camilla Böckelman

  • 1Authors' Affiliations: Institute of Biomedical Technology and BioMediTech, University of Tampere and Tampere University Hospital; Tampere Graduate Program in Biomedicine and Biotechnology (TGPBB), University of Tampere, Tampere; Turku Centre for Biotechnology, University of Turku and Åbo Akademi University; Department of Pathology, University of Turku; Turku Doctoral Program of Biomedical Sciences (TuBS), Turku; Department of Pathology, HUSLAB and Haartman Institute, Helsinki University, Central Hospital and University of Helsinki; University of Helsinki Institute of Biomedicine and Genome-Scale Biology Research Program; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland; Karlsruhe Institute of Technology, Campus North, Institute of Toxicology and Genetics, Karlsruhe, Germany; Adult Cancer Program, Lowy Cancer Centre and Prince of Wales Hospital, UNSW Medicine, University of New South Wales, Sydney, Australia; Department of Medical Biology and Genetics, Faculty of Medicine, Akdeniz University, Antalya, Turkey; Division of Oncology, Children's Hospital of Philadelphia; and Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia.

Cancer Research
|September 28, 2013
PubMed

Insights

New research reveals that inhibiting checkpoint kinase 1 (Chk1) in cancer cells activates protein phosphatase 2A (PP2A), suppressing MYC and impairing cancer cell survival. This mechanism explains Chk1 inhibitor efficacy and identifies CIP2A-PP2A status as a response marker.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Checkpoint kinase 1 (Chk1) is often overactive in cancers, and Chk1 inhibitors show promise as single-agent cancer therapies.
  • A novel mechanism underlying the efficacy of Chk1-targeted therapy in cancer cells has been elucidated.

Purpose of the Study:

  • To uncover a previously unrecognized mechanism contributing to cancer cell response to Chk1-targeted therapy.
  • To investigate the role of protein phosphatase 2A (PP2A) and its inhibitor CIP2A in Chk1 inhibition-mediated anti-cancer effects.

Main Methods:

  • Investigated the effect of Chk1 inhibition on PP2A activity and MYC phosphorylation.
  • Examined the regulation of cancerous inhibitor of PP2A (CIP2A) transcription by Chk1.
  • Utilized in vitro cell culture and in vivo tumor models to assess the impact of modulating Chk1, CIP2A, and PP2A on cancer cell survival and tumor growth.
  • Validated the clinical relevance of CIP2A in human cancer types.

Main Results:

  • Inhibition of Chk1 activity in cancer cells enhances tumor suppressor protein phosphatase 2A (PP2A) activity.
  • PP2A dephosphorylates MYC at serine 62, reducing MYC activity and promoting cancer cell death.
  • Chk1 inhibition decreases the transcription of CIP2A, a key inhibitor of PP2A, thereby activating PP2A.
  • Exogenous expression of CIP2A or blockade of the CIP2A-PP2A complex rescued cancer cell clonogenicity inhibited by Chk1 inhibition.
  • The Chk1-CIP2A-PP2A pathway is regulated by DNA-PK activity and functions independently of p53 or ATM/ATR status.
  • CIP2A was identified as an NMYC-independent prognostic factor in neuroblastoma and other human cancers.

Conclusions:

  • Chk1 inhibition activates PP2A by reducing CIP2A levels, leading to MYC suppression and impaired cancer cell survival, thus explaining the single-agent efficacy of Chk1 inhibitors.
  • The CIP2A-PP2A pathway serves as a pharmacodynamic marker for predicting cancer cell response to Chk1-targeted therapy.

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