Increase in CIP2A expression is associated with doxorubicin resistance

Choi, Yukyung; Park, Jeong Su; Park, Mi Young; Oh, Ki Sook; Lee, Myung Sok; Lim, Jong‐Seok; Kim, Keun Il; Kim, Kun-yong; Kwon, Junhye; Yoon, Do Young; Moon, Eun‐Yi; Yang, Young

doi:10.1016/j.febslet.2011.01.018

Cited by 50 publications

(50 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To circumvent the acknowledged limitations in the repeatability of published microarray results (Ioannidis et al, 2009), the reported CIP2A signature consists only of genes regulated by CIP2A depletion in all five independent sample pairs. All tested signature genes were shown by quantitative RT-PCR to be regulated by CIP2A in four cancer cell lines (Figures 1d and 6e and Supplementary Figures 1B and C) in which CIP2A has previously been shown to be overexpressed (Junttila et al, 2007;Come et al, 2009;Khanna et al, 2009;Choi et al, 2011). Thus, we consider the reported CIP2A signature to be a reliable representation of the transcriptional program driven by CIP2A in human cancer cells.…”

Section: Discussionmentioning

confidence: 98%

CIP2A signature reveals the MYC dependency of CIP2A-regulated phenotypes and its clinical association with breast cancer subtypes

et al. 2012

View full text Add to dashboard Cite

Protein phosphatase 2A (PP2A) is a critical human tumor-suppressor complex. A recently characterized PP2A inhibitor protein, namely cancerous inhibitor of PP2A (CIP2A), has been found to be overexpressed at a high frequency in most of the human cancer types. However, our understanding of gene expression programs regulated by CIP2A is almost absent. Moreover, clinical relevance of the CIP2A-regulated transcriptome has not been addressed thus far. Here, we report a high-confidence transcriptional signature regulated by CIP2A. Bioinformatic pathway analysis of the CIP2A signature revealed that CIP2A regulates several MYC-dependent and MYCindependent gene programs. With regard to MYCindependent signaling, JNK2 expression and transwell migration were inhibited by CIP2A depletion, whereas MYC depletion did not affect either of these phenotypes. Instead, depletion of either CIP2A or MYC inhibited cancer cell colony growth with statistically indistinguishable efficiency. Moreover, CIP2A depletion was shown to regulate the expression of several established MYC target genes, out of which most were MYC-repressed genes. CIP2A small-interfering RNA-elicited inhibition of colony growth or activation of MYC-repressed genes was reversed at large by concomitant PP2A inhibition. Finally, the CIP2A signature was shown to cluster with basal-type and human epidermal growth factor receptor (HER)2-positive (HER2 þ ) breast cancer signatures. Accordingly, CIP2A protein expression was significantly associated with basal-like (P ¼ 0.0014) and HER2 þ (Po0.0001) breast cancers. CIP2A expression also associated with MYC gene amplification (Po0.001). Taken together, identification of CIP2A-driven transcriptional signature, and especially novel MYC-independent signaling programs regulated by CIP2A, provides important resource for understanding CIP2A's role as a clinically relevant human oncoprotein. With regard to MYC, these results both validate CIP2A's role in regulating MYC-mediated gene expression and provide a plausible novel explanation for the high MYC activity in basal-like and HER2 þ breast cancers.

show abstract

Section: Discussionmentioning

confidence: 98%

CIP2A signature reveals the MYC dependency of CIP2A-regulated phenotypes and its clinical association with breast cancer subtypes

et al. 2012

View full text Add to dashboard Cite

show abstract

“…For example, high CIP2A expression predicts poor survival in several types of cancers (10,13,14,36,38). Furthermore, recent reports suggest that CIP2A expression is associated with resistance to several anticancer drugs (14,15,31). Likewise, it has been well established that Plk1 is upregulated in tumors and has been validated as a therapeutic target in many types of cancers (8).…”

Section: Discussionmentioning

confidence: 99%

“…Similar to our observations, several lines of evidence have indicated that cell cycle-arresting agents/conditions modulate CIP2A expression in various cancer cells. For example, serum starvation reduces CIP2A expression in gastric cancer cells and doxorubicin treatment reduces it in p53-proficient cells but not in p53-deficient cells (31,32). Moreover, several cell cycle-promoting factors, such as c-Myc and E2F1, have been reported to stimulate CIP2A expression (12,33).…”

Section: Discussionmentioning

confidence: 99%

CIP2A Modulates Cell-Cycle Progression in Human Cancer Cells by Regulating the Stability and Activity of Plk1

Kim

et al. 2013

Cancer Research

View full text Add to dashboard Cite

Abnormal cell-cycle control can lead to aberrant cell proliferation and cancer. The oncoprotein cancerous inhibitor of protein phosphatase 2A (CIP2A) is an inhibitor of protein phosphatase 2A (PP2A) that stabilizes c-Myc. However, the precise role of CIP2A in cell division is not understood. Herein, we show that CIP2A is required for mitotic progression by regulating the polo-like kinase (Plk1). With mitotic entry, CIP2A translocated from the cytoplasm to the nucleus, where it was enriched at spindle poles. CIP2A depletion delayed mitotic progression, resulting in mitotic abnormalities independent of PP2A activity. Unexpectedly, CIP2A interacted directly with the polo-box domain of Plk1 during mitosis. This interaction was required to maintain Plk1 stability by blocking APC/C-Cdh1-dependent proteolysis, thereby enhancing the kinase activity of Plk1 during mitosis. We observed strong correlation and in vivo interactions between these two proteins in multiple human cancer specimens. Overall, our results established a novel function for CIP2A in facilitating the stability and activity of the pivotal mitotic kinase Plk1 in cell-cycle progression and tumor development. Cancer Res; 73(22); 6667-78. Ó2013 AACR.

show abstract

“…Our findings indicate that CIP2A may be a molecular determinant of bortezomib's sensitivity in leukemia cells. Recently Choi et al 42 also showed that doxorubicin could down-regulate CIP2A. Therefore, anticancer agents that target CIP2A may be an attractive alternative anti-cancer strategy.…”

Section: Discussionmentioning

confidence: 99%

Cancerous inhibitor of protein phosphatase 2A determines bortezomib-induced apoptosis in leukemia cells

Liu

Shiau²,

Kuo³

et al. 2012

Haematologica

View full text Add to dashboard Cite

show abstract

Increase in CIP2A expression is associated with doxorubicin resistance

Cited by 50 publications

References 24 publications

CIP2A signature reveals the MYC dependency of CIP2A-regulated phenotypes and its clinical association with breast cancer subtypes

CIP2A signature reveals the MYC dependency of CIP2A-regulated phenotypes and its clinical association with breast cancer subtypes

CIP2A Modulates Cell-Cycle Progression in Human Cancer Cells by Regulating the Stability and Activity of Plk1

Cancerous inhibitor of protein phosphatase 2A determines bortezomib-induced apoptosis in leukemia cells

Contact Info

Product

Resources

About