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Chk1 Targeting Reactivates PP2A Tumor Suppressor Activity in Cancer Cells

Anchit Khanna, Otto Kauko, Camilla Böckelman, Anni Laine, Ilona Schreck, Johanna I. Partanen, Agnieszka Szwajda, Stefanie Bormann, Turker Bilgen, Merja Helenius, Yuba R. Pokharel, John Pimanda, Mike R. Russel, Caj Haglund, Kristina A. Cole, Juha Klefström, Tero Aittokallio, Carsten Weiss, Ari Ristimäki, Tapio Visakorpi, Jukka Westermarck, Chk1 Targeting Reactivates PP2A Tumor Suppressor Activity in Cancer Cells. Cancer Research 73, 6757–6769, 2013.

Abstract:

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.

BibTeX entry:

@ARTICLE{jKhKaBxLaScPaSzBoBiHePoPiRuHaCoKlAiWeRiViWe13a,
  title = {Chk1 Targeting Reactivates PP2A Tumor Suppressor Activity in Cancer Cells},
  author = {Khanna, Anchit and Kauko, Otto and Böckelman, Camilla and Laine, Anni and Schreck, Ilona and Partanen, Johanna I. and Szwajda, Agnieszka and Bormann, Stefanie and Bilgen, Turker and Helenius, Merja and Pokharel, Yuba R. and Pimanda, John and Russel, Mike R. and Haglund, Caj and Cole, Kristina A. and Klefström, Juha and Aittokallio, Tero and Weiss, Carsten and Ristimäki, Ari and Visakorpi, Tapio and Westermarck, Jukka},
  journal = {Cancer Research},
  volume = {73},
  pages = {6757–6769},
  year = {2013},
}

Belongs to TUCS Research Unit(s): Biomathematics Research Unit (BIOMATH)

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