IJC International Journal of Cancer
Clinical significance of cancerous inhibitor of protein phosphatase 2A in human cancers Anchit Khanna1 and John E. Pimanda1,2 1
Cancerous Inhibitor of Protein Phosphatase 2A (CIP2A), a recently identified oncogene, has emerged as a potential drug target for a range of different tumor types. High CIP2A expression has been reported in almost all solid organ cancers and in some hematological tumors and is associated with high grade and poor prognosis. Notably, high CIP2A expression is determined in over 70% of tumor patient samples in the majority of human cancers. High expression of CIP2A has also been proposed as a useful biomarker that predicts therapeutic response to chemotherapeutics such as Bortezomib, Erlotinib, Checkpoint Kinase 1 inhibitors and pro-senescence based therapies. In this review, we highlight, critically evaluate and discuss the ambiguity in CIP2A’s prognostic role in different human cancers and its role in modulating response and resistance to chemotherapeutics.
Post-translational modifications of proteins are well known to influence their structure, charge and function. These modifications include changes in phosphorylation, ubiquitination, sumoylation, glycosylation, methylation, acetylation, farnecylation and many more. Reversible phosphorylation Key words: P53, PP2A, CIP2A, MYC, CHK1, DNA-PKc, tumor grade, prognostic role, drug resistance, patient stratification, biomarker, personalized medicine Abbreviations: CIP2A: cancerous inhibitor of protein phosphatase 2A; CHK1: checkpoint kinase 1; DNA-PKc: DNA-dependent protein kinase catalytic sub unit; MEFs: mouse embryo fibroblasts; PP2A: protein phosphatase 2A; TIP: T-cell immunomodulatory protein; PME-1: phosphatase methyl esterase-1; EGFR: epidermal growth factor receptor; NSCLC: nonsmall cell lung cancer; TAA: tumor-associated antigen; ELISA: enzyme-linked immune-sorbent assay; HCC: hepatocellular carcinomas; HPV: human papilloma virus; CMM: cutaneous malignant melanoma; PDAC: pancreatic ductal adenocarcinomas; EMT: epithelial-to-mesenchymal transition; CML: chronic myeloid leukemia; AML: acute myeloid leukemia; MYC: myelocytomatosis viral oncogene; HNSCC: head and neck squamous cell carcinomas; TNBC: triple negative breast carcinomas; CSC: cancer stem like-cell Grant sponsor: National Health and Research Medical Council (NH&MRC)-Peter-Doherty Research Fellow; Grant sponsor: National Health and Research Medical Council (NH&MRC), Australia DOI: 10.1002/ijc.29431 History: Received 6 Sep 2014; Accepted 29 Dec 2014; Online 12 Jan 2015 Correspondence to: Dr. Anchit Khanna, Lowy Cancer Research Centre, University of New South Wales, Adult Cancer Program, Level 2, Building C25, Kensington Campus, Sydney, New South Wales 2052, Australia, E-mail: [email protected]
C 2015 UICC Int. J. Cancer: 00, 00–00 (2015) V
was the first of these modifications shown to alter the enzymatic activity of a protein.1 Human kinases and phosphatases are two large gene families that regulate protein phosphorylation and help maintain the balance between phosphorylated and unphosphorylated proteins in the body. These genes act as two opposing switches on specific target proteins. Therefore, perturbation of the activity or expression of protein kinases and phosphatases results in an imbalance in target protein activity, which in turn leads to deregulation of signaling pathways and a variety of disorders, including cancer. As antagonists of oncogenic kinases, many phosphatases exhibit tumor suppressive features.2 In particular, some of the Protein Phosphatase 2A (PP2A) complexes have emerged as major tumor suppressors, mainly because of their opposing action on a number of oncogenic processes such as cellular migration,3 transformation,4–6 apoptosis,7 senescence,8 proliferation9 and aberrant cell cycle effects.10 However, despite the frequency of reduced PP2A activity in human cancers, DNA mutations in their constituent genes are rare.4 This suggests that there may exist alternative mechanisms by which PP2A activity is inhibited in human cancers. In recent years, several cellular proteins that inhibit PP2A activity in tumors, e.g., SET (SET nuclear oncogene), T-cell Immunomodulatory Protein (TIP), Phosphatase Methyl Esterase-1 (PME-1) and Cancerous Inhibitor of Protein Phosphatase 2A (CIP2A) have been identified.6 Of these, CIP2A has emerged as one of the most frequently altered proteins in human cancers.11–13 CIP2A is a recently identified endogenous inhibitor of PP2A, which as its name suggests, inhibits the tumor suppressive activity of the PP2A complex and promotes cancer.14 This oncoprotein was first identified as an auto-antigen using serum autoantibody in gastric cancer.15 It was initially labelled as p90 based on its size of 90 kD. Notably, CIP2A
Mini Review
Lowy Cancer Research Centre and Prince of Wales Clinical School, University of New South Wales (UNSW) Medicine Department, Sydney, New South Wales 2052, Australia 2 Department of Haematology, the Prince of Wales Hospital, Randwick, New South Wales, Australia
CIP2A in human cancers
Mini Review
2
Figure 1. Role of CIP2A expression as a clinically relevant biomarker. An overview of different reports implicating high CIP2A expression with clinical prognosis (blue star) or high-grade disease and disease progression (pink sphere). The number of CIP2A positive samples in each study shown as a percentage. Image of the human body courtesy http://www.sciencekids.co.nz/pictures/humanbody/humanorgans. html [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
overexpression is seen in over 70% of patient samples of most solid organ and haematological malignancies (Fig. 1). Given the relatively low levels of CIP2A expression in normal tissues (with the exception of the testis), this protein is of considerable interest to cancer biologists as a promising drug target.12,16–23 This is substantiated by the fact that CIP2A hypomorphic (HO) mice, generated using gene-trap technology, have normal life span without any severe developmental defects.24 Furthermore, mouse embryo fibroblasts (MEFs) isolated from these homozygous mutated CIP2A mice undergo growth arrest and have increased SA-b-gal staining, a marker of senescence, with flattened cell morphology.18 The regulation and mechanisms by which CIP2A promotes carcinogenesis has been extensively reviewed recently.11,12 Here, we review the prognostic value of CIP2A expression in different human cancers, and the role of CIP2A in conferring resistance to various anticancer agents.
Prognostic Role of CIP2A Expression and Its Correlation with Pathological Variables in Human Cancers The prognostic role of CIP2A expression was established for the first time in subgroups of gastric cancer patients, i.e.,
tumor size
Clinical significance of cancerous inhibitor of protein phosphatase 2A in human cancers Anchit Khanna1 and John E. Pimanda1,2 1
Cancerous Inhibitor of Protein Phosphatase 2A (CIP2A), a recently identified oncogene, has emerged as a potential drug target for a range of different tumor types. High CIP2A expression has been reported in almost all solid organ cancers and in some hematological tumors and is associated with high grade and poor prognosis. Notably, high CIP2A expression is determined in over 70% of tumor patient samples in the majority of human cancers. High expression of CIP2A has also been proposed as a useful biomarker that predicts therapeutic response to chemotherapeutics such as Bortezomib, Erlotinib, Checkpoint Kinase 1 inhibitors and pro-senescence based therapies. In this review, we highlight, critically evaluate and discuss the ambiguity in CIP2A’s prognostic role in different human cancers and its role in modulating response and resistance to chemotherapeutics.
Post-translational modifications of proteins are well known to influence their structure, charge and function. These modifications include changes in phosphorylation, ubiquitination, sumoylation, glycosylation, methylation, acetylation, farnecylation and many more. Reversible phosphorylation Key words: P53, PP2A, CIP2A, MYC, CHK1, DNA-PKc, tumor grade, prognostic role, drug resistance, patient stratification, biomarker, personalized medicine Abbreviations: CIP2A: cancerous inhibitor of protein phosphatase 2A; CHK1: checkpoint kinase 1; DNA-PKc: DNA-dependent protein kinase catalytic sub unit; MEFs: mouse embryo fibroblasts; PP2A: protein phosphatase 2A; TIP: T-cell immunomodulatory protein; PME-1: phosphatase methyl esterase-1; EGFR: epidermal growth factor receptor; NSCLC: nonsmall cell lung cancer; TAA: tumor-associated antigen; ELISA: enzyme-linked immune-sorbent assay; HCC: hepatocellular carcinomas; HPV: human papilloma virus; CMM: cutaneous malignant melanoma; PDAC: pancreatic ductal adenocarcinomas; EMT: epithelial-to-mesenchymal transition; CML: chronic myeloid leukemia; AML: acute myeloid leukemia; MYC: myelocytomatosis viral oncogene; HNSCC: head and neck squamous cell carcinomas; TNBC: triple negative breast carcinomas; CSC: cancer stem like-cell Grant sponsor: National Health and Research Medical Council (NH&MRC)-Peter-Doherty Research Fellow; Grant sponsor: National Health and Research Medical Council (NH&MRC), Australia DOI: 10.1002/ijc.29431 History: Received 6 Sep 2014; Accepted 29 Dec 2014; Online 12 Jan 2015 Correspondence to: Dr. Anchit Khanna, Lowy Cancer Research Centre, University of New South Wales, Adult Cancer Program, Level 2, Building C25, Kensington Campus, Sydney, New South Wales 2052, Australia, E-mail: [email protected]
C 2015 UICC Int. J. Cancer: 00, 00–00 (2015) V
was the first of these modifications shown to alter the enzymatic activity of a protein.1 Human kinases and phosphatases are two large gene families that regulate protein phosphorylation and help maintain the balance between phosphorylated and unphosphorylated proteins in the body. These genes act as two opposing switches on specific target proteins. Therefore, perturbation of the activity or expression of protein kinases and phosphatases results in an imbalance in target protein activity, which in turn leads to deregulation of signaling pathways and a variety of disorders, including cancer. As antagonists of oncogenic kinases, many phosphatases exhibit tumor suppressive features.2 In particular, some of the Protein Phosphatase 2A (PP2A) complexes have emerged as major tumor suppressors, mainly because of their opposing action on a number of oncogenic processes such as cellular migration,3 transformation,4–6 apoptosis,7 senescence,8 proliferation9 and aberrant cell cycle effects.10 However, despite the frequency of reduced PP2A activity in human cancers, DNA mutations in their constituent genes are rare.4 This suggests that there may exist alternative mechanisms by which PP2A activity is inhibited in human cancers. In recent years, several cellular proteins that inhibit PP2A activity in tumors, e.g., SET (SET nuclear oncogene), T-cell Immunomodulatory Protein (TIP), Phosphatase Methyl Esterase-1 (PME-1) and Cancerous Inhibitor of Protein Phosphatase 2A (CIP2A) have been identified.6 Of these, CIP2A has emerged as one of the most frequently altered proteins in human cancers.11–13 CIP2A is a recently identified endogenous inhibitor of PP2A, which as its name suggests, inhibits the tumor suppressive activity of the PP2A complex and promotes cancer.14 This oncoprotein was first identified as an auto-antigen using serum autoantibody in gastric cancer.15 It was initially labelled as p90 based on its size of 90 kD. Notably, CIP2A
Mini Review
Lowy Cancer Research Centre and Prince of Wales Clinical School, University of New South Wales (UNSW) Medicine Department, Sydney, New South Wales 2052, Australia 2 Department of Haematology, the Prince of Wales Hospital, Randwick, New South Wales, Australia
CIP2A in human cancers
Mini Review
2
Figure 1. Role of CIP2A expression as a clinically relevant biomarker. An overview of different reports implicating high CIP2A expression with clinical prognosis (blue star) or high-grade disease and disease progression (pink sphere). The number of CIP2A positive samples in each study shown as a percentage. Image of the human body courtesy http://www.sciencekids.co.nz/pictures/humanbody/humanorgans. html [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
overexpression is seen in over 70% of patient samples of most solid organ and haematological malignancies (Fig. 1). Given the relatively low levels of CIP2A expression in normal tissues (with the exception of the testis), this protein is of considerable interest to cancer biologists as a promising drug target.12,16–23 This is substantiated by the fact that CIP2A hypomorphic (HO) mice, generated using gene-trap technology, have normal life span without any severe developmental defects.24 Furthermore, mouse embryo fibroblasts (MEFs) isolated from these homozygous mutated CIP2A mice undergo growth arrest and have increased SA-b-gal staining, a marker of senescence, with flattened cell morphology.18 The regulation and mechanisms by which CIP2A promotes carcinogenesis has been extensively reviewed recently.11,12 Here, we review the prognostic value of CIP2A expression in different human cancers, and the role of CIP2A in conferring resistance to various anticancer agents.
Prognostic Role of CIP2A Expression and Its Correlation with Pathological Variables in Human Cancers The prognostic role of CIP2A expression was established for the first time in subgroups of gastric cancer patients, i.e.,
tumor size
