Review Cancerous Inhibitor of Protein Phosphatase 2A, an Emerging Human Oncoprotein and a Potential Cancer Therapy Target Anchit Khanna 1,2 , John E. Pimanda 1,2 , and Jukka Westermarck 3,4 Abstract Protein phosphatase 2A (PP2A) complexes function as tumor suppressors by inhibiting the activity of several critical oncogenic signaling pathways. Consequently, inhibition of the PP2A phosphatase activity is one of many prerequisites for the transformation of normal human cells into cancerous cells. However, mechanisms for PP2A inactivation in human cancers are poorly understood. The aberrant expression of cancerous inhibitor of protein phosphatase 2A (CIP2A), a recently identified endogenous PP2A inhibitor in malignant cells, is one such mechanism. Various independent studies have validated CIP2A's role in promoting tumor growth and resistance to apoptosis and senescence-inducing therapies. Notably, high CIP2A expression predicts poor patient prognosis in several human cancer types. Among the oncogenic proteins dephosphorylated by PP2A, the MYC oncoprotein, which is phosphorylated at serine 62, has surfaced as a marker for the oncogenic activity of CIP2A. The positive- feedback loop between CIP2A and MYC augments the activity of MYC in cancer cells. In addition, CIP2A promotes the phosphorylation and activity of additional oncoproteins, including E2F1 and AKT. However, CIP2A is not essential for normal mouse growth and development. These findings indicate that CIP2A is a novel anticancer target based on PP2A reactivation and inhibition of the oncogenic activity of its downstream effectors. The potential approaches and feasibility of targeting CIP2A are discussed here. Cancer Res; 73(22); 6548–53. Ó2013 AACR. Introduction Reversible protein phosphorylation is one of the most common mechanisms for regulating protein function and transmitting signals throughout the cell. Phosphoregulation is tightly controlled by protein kinases and phosphatases, and these two classes of enzymes thus act as complementary molecular switches to determine the phosphorylation status of a large fraction of the human proteome. It has become evident that the deregulation of this balance contributes to the pathogenesis of several human diseases, including cancer. Constitutively activated protein kinase driver mutations are found in many cancers, and they constitute an important class of cancer therapy target proteins (1). However, despite the relative effectiveness of kinase inhibitors as cancer drugs, most cancers eventually become resistant to these inhibitors (1). This limitation, in addition to the limited number of drug targetable kinases, creates an urgent need to develop and implement new strategies to prolong the survival of cancer patients. As phosphatases are equally important for determin- ing the phosphorylation status of oncogenic phosphoproteins, increasing the activity of tumor suppressor phosphatases is an alternative or complementary strategy to target increased phosphorylation-dependent signaling in cancer cells (2, 3). However, the feasibility and potential of this cancer therapy strategy remain largely unexplored. A critical role for inhibition of phosphatase activity in cancer is strongly supported by functional experiments using immor- talized human cells. Findings from several independent studies demonstrate that activation of kinase signaling via the expres- sion of the activated RAS oncoprotein is not sufficient to transform immortalized cells if the major human serine/thre- onine phosphatase complex, protein phosphatase 2A (PP2A), is not simultaneously inhibited (3). These results strongly sup- port the rationale for PP2A reactivation in combination with kinase signaling inhibition as an effective approach for cancer therapy (2, 3). Of the various phosphatases, PP1 and PP2A account for most of the serine/threonine phosphatase activity in the cell (2, 3). The first indication that PP1 and PP2A complexes have tumor suppressor activities was obtained from studies using the serine/threonine phosphatase inhibitor okadaic acid, which is a potent inhibitor of PP2A but also inhibits PP1 at higher concentrations (2, 3). The potential relevance of PP1 inhibition and specific PP1 inhibitors, such as NIPP1 and DARPP-32, for cancer is still emerging, but the subsequent work has estab- lished the role of PP2A as an important human tumor sup- pressor (2–4). PP2A is a trimeric complex consisting of the scaffolding A-subunit, the catalytic C-subunit, and various Authors' Affiliations: 1 Adult Cancer Program, Lowy Cancer Research Centre and Prince of Wales Hospital, University of New South Wales (UNSW) Medicine; 2 Translational Cancer Research Network, University of New South Wales (UNSW), Sydney, Australia; 3 Turku Centre for Biotech- nology, University of Turku and Åbo Akademi University; and 4 Department of Pathology, University of Turku, Turku, Finland Corresponding Authors: A. Khanna, University of New South Wales (UNSW), Level2, Kensington Campus, Building C25, Sydney, NSW 2052, Australia. Phone: 61-2-9385-2527; Fax: 61-2-9385-1510; E-mail: a.khanna@unsw.edu.au; and J. Westermarck, jukka.westermarck@utu.fi doi: 10.1158/0008-5472.CAN-13-1994 Ó2013 American Association for Cancer Research. 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