title: Cancerous inhibitor of protein phosphatase 2A, an emerging human oncoprotein and a potential cancer therapy target.
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.
authors.affiliation: Authors' Affiliations: Adult Cancer Program, Lowy Cancer Research Centre and Prince of Wales Hospital, University of New South Wales (UNSW) Medicine; Translational Cancer Research Network, University of New South Wales (UNSW), Sydney, Australia; Turku Centre for Biotechnology, University of Turku and Åbo Akademi University; and Department of Pathology, University of Turku, Turku, Finland.
authors.forename: Anchit
authors.initials: A
authors.lastname: Khanna
authors.forename: John E
authors.initials: JE
authors.lastname: Pimanda
authors.forename: Jukka
authors.initials: J
authors.lastname: Westermarck
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000502:physiology*; D002471:Cell Transformation, Neoplastic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D051379:Mice; D058990:Molecular Targeted Therapy / Q000379:methods*; D009369:Neoplasms / Q000235:genetics* / Q000628:therapy*; D015513:Oncogene Proteins / Q000502:physiology*; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D001324:Autoantigens; C500266:CIP2A protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D015513:Oncogene Proteins; D054648:Protein Phosphatase 2