Chk1 targeting reactivates PP2A tumor suppressor activity in cancer cells.
Checkpoint kinase Chk1 is constitutively active in many cancer cell types and new generation Chk1 inhibitors show marked antitumor activity as single agents. Here we present a hitherto unrecognized mechanism that contributes to the response of cancer cells to Chk1-targeted therapy. Inhibiting chronic Chk1 activity in cancer cells induced the tumor suppressor activity of protein phosphatase protein phosphatase 2A (PP2A), which by dephosphorylating MYC serine 62, inhibited MYC activity and impaired cancer cell survival. Mechanistic investigations revealed that Chk1 inhibition activated PP2A by decreasing the transcription of cancerous inhibitor of PP2A (CIP2A), a chief inhibitor of PP2A activity. Inhibition of cancer cell clonogenicity by Chk1 inhibition could be rescued in vitro either by exogenous expression of CIP2A or by blocking the CIP2A-regulated PP2A complex. Chk1-mediated CIP2A regulation was extended in tumor models dependent on either Chk1 or CIP2A. The clinical relevance of CIP2A as a Chk1 effector protein was validated in several human cancer types, including neuroblastoma, where CIP2A was identified as an NMYC-independent prognostic factor. Because the Chk1-CIP2A-PP2A pathway is driven by DNA-PK activity, functioning regardless of p53 or ATM/ATR status, our results offer explanative power for understanding how Chk1 inhibitors mediate single-agent anticancer efficacy. Furthermore, they define CIP2A-PP2A status in cancer cells as a pharmacodynamic marker for their response to Chk1-targeted therapy.
Authors' 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.
Anchit
A
Khanna
Otto
O
Kauko
Camilla
C
Böckelman
Anni
A
Laine
Ilona
I
Schreck
Johanna I
JI
Partanen
Agnieszka
A
Szwajda
Stefanie
S
Bormann
Turker
T
Bilgen
Merja
M
Helenius
Yuba R
YR
Pokharel
John
J
Pimanda
Mike R
MR
Russel
Caj
C
Haglund
Kristina A
KA
Cole
Juha
J
Klefström
Tero
T
Aittokallio
Carsten
C
Weiss
Ari
A
Ristimäki
Tapio
T
Visakorpi
Jukka
J
Westermarck
D001324:Autoantigens / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D000071877:Checkpoint Kinase 1; D004789:Enzyme Activation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism*; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D001324:Autoantigens; C500266:CIP2A protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D047428:Protein Kinase Inhibitors; D025521:Tumor Suppressor Proteins; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C517189:PPP2CA protein, human; D054648:Protein Phosphatase 2