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B55β-associated PP2A complex controls PDK1-directed myc signaling and modulates rapamycin sensitivity in colorectal

Jing Tan1, Puay Leng Lee, Zhimei Li

  • 1Cancer Biology and Pharmacology, Genome Institute of Singapore, Agency for Science, Technology and Research, Biopolis, Singapore.

Cancer Cell
|November 16, 2010
PubMed

Insights

The PP2A-B55β protein phosphatase is inactivated in colorectal cancer, leading to resistance against rapamycin by promoting Myc phosphorylation. Restoring PP2A-B55β sensitizes cancer cells to rapamycin.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • The PP2A (protein phosphatase 2A) serine/threonine protein phosphatase is a key regulator of cell growth, proliferation, and survival.
  • Alterations in the PP2A pathway contributing to cancer growth advantage are not well understood.

Purpose of the Study:

  • To investigate the role of the PP2A complex, specifically the B55β regulatory subunit (encoded by PPP2R2B), in colorectal cancer.
  • To elucidate the mechanism by which PP2A-B55β influences cancer cell signaling and response to rapamycin treatment.

Main Methods:

  • Analysis of PPP2R2B epigenetic inactivation via DNA hypermethylation in colorectal cancer.
  • Investigation of the interaction between PP2A-B55β and PDK1 (3-phosphoinositide-dependent kinase 1) concerning Myc phosphorylation.
  • Assessment of rapamycin-induced Myc phosphorylation in the context of PPP2R2B loss and its dependence on PDK1, PI3K, and AKT.
  • Evaluation of the effects of PPP2R2B reexpression or PDK1 inhibition on rapamycin sensitivity.

Main Results:

  • PPP2R2B is epigenetically inactivated by DNA hypermethylation in colorectal cancer.
  • PP2A-B55β interacts with PDK1 and regulates its activity towards Myc phosphorylation.
  • Loss of PPP2R2B leads to compensatory Myc phosphorylation, mediated by PDK1 in a PI3K/AKT-independent manner, conferring resistance to rapamycin.
  • Reexpression of PPP2R2B, PDK1 genetic ablation, or PDK1 inhibition abrogates rapamycin-induced Myc phosphorylation and restores rapamycin sensitivity.

Conclusions:

  • PP2A-B55β antagonizes PDK1-Myc signaling.
  • The PP2A-B55β pathway is a critical modulator of rapamycin sensitivity in colorectal cancer.
  • Targeting the PP2A-B55β-PDK1-Myc axis may offer therapeutic strategies for overcoming rapamycin resistance.

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