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Protein phosphatase 2A (PP2A), a drugable tumor suppressor in Ph1(+) leukemias

Abstract

Protein phosphatase-2A (PP2A) is one of the major cellular serine-threonine phosphatases and is involved in the regulation of cell homeostasis through the negative regulation of signaling pathways initiated by protein kinases. As several cancers are characterized by the aberrant activity of oncogenic kinases, it was not surprising that a phosphatase like PP2A has progressively been considered as a potential tumor suppressor. Indeed, multiple solid tumors (e.g. melanomas, colorectal carcinomas, lung and breast cancers) present with genetic and/or functional inactivation of different PP2A subunits and, therefore, loss of PP2A phosphatase activity towards certain substrates. Likewise, impaired PP2A phosphatase activity has been linked to B-cell chronic lymphocytic leukemia, Philadelphia-chromosome positive acute lymphoblastic leukemia and blast crisis chronic myelogenous leukemia. Remarkably, drugs such as forskolin, 1,9-dideoxy-forskolin and FTY720 which lead to PP2A activation effectively antagonize leukemogenesis in both in vitro and in vivo models of these cancers. Thus, PP2A is now in the spotlight as a highly promising drugable target for the development of a new series of anticancer agents potentially capable of overcoming drug-resistance induced in patients by continuous exposure to kinase inhibitor monotherapy. Herein, we review current knowledge of PP2A biology and function with particular emphasis on its tumor suppressor activity and possible therapeutic implications in cancer.

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Abbreviations

ALL:

acute lymphoblastic leukemia

CML:

chronic myelogenous leukemia

hnRNP:

heterogeneous nuclear ribonucleoprotein

MAPK:

mitogen activated protein kinase

Ph:

philadelphia chromosome

PP2A:

protein phosphatase 2A

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Acknowledgments

This work was supported in part by grants from the National Cancer Institute CA095512 (D.P.), NIH, Bethesda, MD; the US Army, Chronic Myelogenous Leukemia Research Program, DAMD17-03-1-0184 and W81XWH-07-1-0270 (D.P) and by the American-Italian Cancer Foundation (P.N). D.P. is a Scholar of the Leukemia and Lymphoma Society. The use of PP2A activating drugs for the treatment of Ph1 leukemias is currently patent pending: Perrotti D et al. (PCT/US2006/10882) “Activation of PP2A in the Treatment of Ph1 Leukemias” Application Serial Number: 60/665,091 final application pending.

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Correspondence to Danilo Perrotti.

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Perrotti, D., Neviani, P. Protein phosphatase 2A (PP2A), a drugable tumor suppressor in Ph1(+) leukemias. Cancer Metastasis Rev 27, 159–168 (2008). https://doi.org/10.1007/s10555-008-9119-x

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Keywords

  • Leukemia
  • BCR/ABL
  • PP2A
  • FTY720
  • Phosphatase