CIP2A is over‐expressed in acute myeloid leukaemia and associated with HL60 cells proliferation and differentiation

Wang, J.; Li, W.; Li, L.; Yu, Xiaolin; Jia, Jihui; Chen, C.

doi:10.1111/j.1751-553x.2010.01288.x

Cited by 58 publications

(49 citation statements)

References 28 publications

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“…It has been shown that CIP2A deletion results in a reduction of oncogenic potential for multiple tumors (20,26,32). Furthermore, SET knockdown was shown to negatively affect tumorigenesis in blast crisis chronic myelogenous leukemia (33).…”

Section: Discussionmentioning

confidence: 99%

Targeting c-MYC by antagonizing PP2A inhibitors in breast cancer

Janghorban¹,

Farrell²,

Allen-Petersen³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

168

175

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The transcription factor c-MYC is stabilized and activated by phosphorylation at serine 62 (S62) in breast cancer. Protein phosphatase 2A (PP2A) is a critical negative regulator of c-MYC through its ability to dephosphorylate S62. By inactivating c-MYC and other key signaling pathways, PP2A plays an important tumor suppressor function. Two endogenous inhibitors of PP2A, I2PP2A, Inhibitor-2 of PP2A (SET oncoprotein) and cancerous inhibitor of PP2A (CIP2A), inactivate PP2A and are overexpressed in several tumor types. Here we show that SET is overexpressed in about 50-60% and CIP2A in about 90% of breast cancers. Knockdown of SET or CIP2A reduces the tumorigenic potential of breast cancer cell lines both in vitro and in vivo. Treatment of breast cancer cells in vitro or in vivo with OP449, a novel SET antagonist, also decreases the tumorigenic potential of breast cancer cells and induces apoptosis. We show that this is, at least in part, due to decreased S62 phosphorylation of c-MYC and reduced c-MYC activity and target gene expression. Because of the ubiquitous expression and tumor suppressor activity of PP2A in cells, as well as the critical role of c-MYC in human cancer, we propose that activation of PP2A (here accomplished through antagonizing endogenous inhibitors) could be a novel antitumor strategy to posttranslationally target c-MYC in breast cancer.breast cancer therapy | phosphatase activator T he c-MYC (MYC) oncoprotein is overexpressed in human breast cancer and this is associated with poor clinical outcome (1, 2). Expression of MYC is regulated at multiple levels, including protein stability, which is increased in several cancer types (1,3,4). MYC stability is regulated in part by sequential and interdependent phosphorylation at two conserved residues, threonine 58 (T58) and serine 62 (S62) (5). MYC is phosphorylated at S62 (pS62) through the mitogen-activated protein kinase (MAPK) pathway or cyclin-dependent kinase (CDK) activation in response to growth signals and this modification increases its stability and oncogenic activity (5-8). When growth signals cease, GSK3, in a manner dependent upon prior phosphorylation at S62, phosphorylates T58 (pT58) (5, 6). T58 phosphorylation facilitates protein phosphatase 2A (PP2A)-mediated dephosphorylation of pS62 and recruitment of the E3 ubiquitin ligase SCF Fbw7 to initiate proteasomal destruction of MYC (9, 10). This process is facilitated by AXIN1, which helps nucleate a destruction complex for MYC at target gene promoters (11, 12). Our previous work has shown that MYC stability is increased in breast cancers and that this correlates with high pS62-and low pT58-MYC (4).PP2A is a ubiquitously expressed, heterotrimeric serinethreonine (S/T) phosphatase that mediates 30-50% of cellular S/T phosphatase activity (13). Target specificity of PP2A is directed by a variable regulatory (B) subunit, and we have shown that B56α is the isoform that directs PP2A to MYC (9, 13). Human cell transformation requires inhibition of PP2A activity and, in an siRNA screen, B56α, ...

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Section: Discussionmentioning

confidence: 99%

Targeting c-MYC by antagonizing PP2A inhibitors in breast cancer

Janghorban¹,

Farrell²,

Allen-Petersen³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

168

175

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“…16 CIP2A has recently been shown to be overexpressed in AML patients and correlated with relapse after treatment. 17 A single case study has reported a CIP2A-MLL translocation in infant AML. 18 Nothing is known about CIP2A expression and function in CML.…”

Section: Introductionmentioning

confidence: 99%

Cancerous inhibitor of PP2A (CIP2A) at diagnosis of chronic myeloid leukemia is a critical determinant of disease progression

Lucas

Harris

Giannoudis

et al. 2011

Blood

123

121

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Prospective identification of patients whose chronic myeloid leukemia (CML) will progress to blast crisis is currently not possible. PP2A is a phosphatase and tumor suppressor that regulates cell proliferation, differentiation, and survival. Cancerous inhibitor of PP2A (CIP2A) is a recently described inhibitor of PP2A in breast and gastric cancer. The aim of this study was to investigate whether CIP2A played a role in CML and whether PP2A or its inhibitor proteins CIP2A or SET could predict clinical outcome. At the time of diagnosis of CML, patients who will later progress to blast crisis have significantly higher levels of CIP2A protein (P < .0001) than patients who do not progress, suggesting that PP2A is functionally inactive. We show that the potential mechanism for disease progression is via altered phosphorylation of the oncogene c-Myc. Knockdown of CIP2A results in increased PP2A activity, decreased c-Myc levels, and a decrease in BCR-ABL1 tyrosine kinase activity. We demonstrate that CIP2A levels at diagnosis can consistently predict patients who will progress to blast crisis. The data show that CIP2A is biologically and clinically important in CML and may be a novel therapeutic target. (Blood. 2011;117(24):6660-6668) IntroductionChronic myeloid leukemia (CML) is a malignant disease of the primitive hematologic cell, characterized by inappropriate expansion of myeloid cells. Although this disease is readily controlled by imatinib, approximately one-third of patients will eventually fail treatment 1,2 ; and a significant proportion of these will progress toward blast crisis (BC), which is usually rapidly fatal. Poor response to imatinib and progression to BC have been linked to high BCR-ABL1 tyrosine kinase activity, 3 but why one patient can remain in well-controlled chronic phase for decades whereas another may rapidly progress to BC is poorly understood.The BCR-ABL1 tyrosine kinase in CML is responsible for growth and survival of the malignant cells through activation of signaling pathways, such as the mitogen-activated protein kinase cascade and the PI3K pathway. 4,5 A major cellular serine/threonine phosphatase working to down-regulate activation of these pathways is the tumor suppressor protein phosphatase 2A (PP2A). 6 In CML cells, PP2A is a key target of BCR-ABL1 signaling; this protein becomes inactivated in these cells because BCR-ABL1 stimulates prevention of its auto-dephosphorylation at tyrosine 307 . 7,8 Maintenance of pY 307 -PP2A levels in CML cells feeds back to BCR-ABL1 and facilitates increased and sustained kinase activity. Inhibition of BCR-ABL1 by imatinib results in reactivation of PP2A, inducing both suppression of growth and enhanced apoptosis of the leukemic cells. 8 However, it is unknown whether Y 307 in PP2A is a direct substrate of BCR-ABL1, and the mechanism regulating phosphorylation of PP2A at this site is not clearly defined.One proposal for the mechanism through which BCR-ABL1 regulates PP2A activity in CML cells involves expression of the PP2A inhibitor protein SET. In ...

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“…CIP2A is a widespread oncogenic factor in human neoplasms (4)(5)(6)(7)(8)(9)3). Similar to the Ras oncogene, CIP2A is required for anchorage-independent cell growth and malignant transformation of human cells (4).…”

Section: A B C Discussionmentioning

confidence: 99%

“…Previous studies have shown that CIP2A serves a critical role in the progression of several cancer types, including head and neck squamous cell carcinoma, oral squamous cell carcinoma, oesophageal squamous cell carcinoma, colon, gastric, breast, prostate, tongue, lung, cervical cancer and acute myeloid leukaemia (3)(4)(5)(6)(7)(8)(9). In 2009, Côme et al (10) demonstrated that CIP2A is associated with clinical aggressivity in human breast cancer and promotes the malignant growth of breast cancer cells (10).…”

Section: Introductionmentioning

confidence: 99%

Expression of cancerous inhibitor of protein phosphatase 2A in human triple negative breast cancer correlates with tumor survival, invasion and autophagy

Feng

Guo

et al. 2016

Oncology Letters

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Abstract. Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a recently characterized oncoprotein which is involved in the progression of several human malignancies. The present study aimed to investigate its biological function in human triple negative breast cancer (TNBC). The expression of CIP2A in TNBC cells was examined and it was observed that CIP2A was elevated in the TNBC cell line compared with poorly invasive breast cancer cells. CIP2A depletion in TNBC cell lines inhibited proliferation, and induced apoptosis and autophagy. In addition, CIP2A depletion inhibited invasion and migration of TNBC cells. Furthermore, CIP2A depletion downregulated Akt/mTOR/P70S6K phosphorylation. These results validate the role of CIP2A as a invasion-associated oncoprotein and established CIP2A as a promising therapeutic target of TNBC.

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CIP2A is over‐expressed in acute myeloid leukaemia and associated with HL60 cells proliferation and differentiation

Cited by 58 publications

References 28 publications

Targeting c-MYC by antagonizing PP2A inhibitors in breast cancer

Targeting c-MYC by antagonizing PP2A inhibitors in breast cancer

Cancerous inhibitor of PP2A (CIP2A) at diagnosis of chronic myeloid leukemia is a critical determinant of disease progression

Expression of cancerous inhibitor of protein phosphatase 2A in human triple negative breast cancer correlates with tumor survival, invasion and autophagy

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