CIP2A expression and localization in oral carcinoma and dysplasia

Katz, Joseph; Jakymiw, Andrew; Ducksworth, Monet K.; Stewart, Carol M.; Bhattacharyya, Indraneel; Cha, Seunghee; Chan, Edward K. L.

doi:10.4161/cbt.10.7.12895

Cited by 46 publications

(40 citation statements)

References 17 publications

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“…Recently, multiple publications have also described increased expression of CIP2A in various types of cancer cells and tumor samples, including gastric, breast, prostate, cervical, ovarian and colorectal cancer and a variety of other cancers. 7,8,[11][12][13][14][15][16][17][18][19][20][21][22][23][24] These observations suggest a direct correlation between CIP2A overexpression, cancer progression, aggressivity and poor prognosis in cancer patients. 11,16 We are the first to elucidate the transcriptional regulation of CIP2A in female urogenital cancers.…”

Section: Discussionmentioning

confidence: 81%

“…Similarly, an increase in CIP2A expression has been observed in tissue samples obtained from gastric, breast, oral, prostate, cervical, esophageal squamous cell, non-small cell lung, colon, ovarian and colorectal cancer patients. [11][12][13][14][15][16][17][18][19] The overexpression of CIP2A in breast, non-small cell lung and early stage tongue cancer has been correlated with poor prognosis, suggesting that CIP2A levels could serve as a marker for disease progression. 11,16,20 Coenen et al 21 demonstrated CIP2A to be a novel mixed lineage leukemia translocation partner in acute myeloid leukemia (AML) patients.…”

Section: Ets1 and Elk1 Transcription Factors Regulate Cancerous Inhibmentioning

confidence: 99%

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Ets1 and Elk1 transcription factors regulatecancerous inhibitor of protein phosphatase 2Aexpression in cervical and endometrial carcinoma cells

et al. 2012

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Section: Discussionmentioning

confidence: 81%

Section: Ets1 and Elk1 Transcription Factors Regulate Cancerous Inhibmentioning

confidence: 99%

Ets1 and Elk1 transcription factors regulatecancerous inhibitor of protein phosphatase 2Aexpression in cervical and endometrial carcinoma cells

et al. 2012

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“…CIP2A depletion results in inhibition of malignant cell growth and inhibition of tumor growth in mouse xenograft models (Junttila et al, 2007;Come et al, 2009). CIP2A is overexpressed in most major solid human cancer types, including head and neck squamous cell carcinomas as well as gastric, esophageal, breast, colon, lung and prostate cancer (Junttila et al, 2007;Li et al, 2008;Come et al, 2009;Khanna et al, 2009;Dong et al, 2010;Katz et al, 2010;Qu et al, 2010;Vaarala et al, 2010). Strikingly, with the exception of breast cancer, in which 40% of patient samples overexpress CIP2A (Come et al, 2009), all other studied human cancer types have CIP2A overexpression in 65-90% of patient samples.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2012

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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.

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“…Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a cellular protein phosphatase 2A (PP2A) inhibitor that inhibits proteolytic degradation of c-Myc (Junttila et al, 2007) and is overexpressed in several human epithelial malignancies, including NSCLC (Soo Hoo et al, 2002;Junttila et al, 2007;Côme et al 2009;Khanna et al, 2009;Katz et al, 2010;Vaarala et al, 2010;Dong et al, 2011;Ma et al, 2011;Xu et al, 2012). Overexpression of CIP2A in NSCLC correlates with poor prognosis (Dong et al, 2011;Ma et al, 2011;Xu et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

TD-19, an Erlotinib Derivative, Induces Epidermal Growth Factor Receptor Wild-Type Nonsmall-Cell Lung Cancer Apoptosis through CIP2A-Mediated Pathway

Chao¹,

Wang²,

Lai

et al. 2014

J Pharmacol Exp Ther

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Some patients with nonsmall-cell lung cancer (NSCLC) without epidermal growth factor receptor (EGFR) mutations still respond to gefitinib and erlotinib, suggesting that there may be a mechanism(s) other than the EGFR pathway that mediates the tumoricidal effects. In the current study, we tested the efficacy of TD-19, a novel compound chemically modified from erlotinib, which has more potent apoptotic effects than erlotinib in EGFR wild-type NSCLC cell lines. TD-19 induced significant cell death and apoptosis in H358, H441, H460, and A549 cells, as evidenced by increased caspase-3 activity and cleavage of procaspase-9 and poly (ADP-ribose) polymerase. The apoptotic effect of TD-19 in H460 cells, which were resistant to erlotinib, was associated with downregulation of cancerous inhibitor of protein phosphatase 2A (CIP2A), increased protein phosphatase 2A (PP2A) activity, and decreased AKT phosphorylation, but minimal effects on EGFR phosphorylation. Overexpression of CIP2A partially protected the H460 cells from TD-19-induced apoptosis. Okadaic acid, a known PP2A inhibitor, significantly reduced TD-19-induced apoptosis, while forskolin, which increased PP2A activity, increased the apoptotic effect of TD-19. TD-19 inhibited the growth of H460 xenograft tumors by ∼80%. We conclude that TD-19 exerted tumoricidal effects on NSCLC cells. TD-19 provides proof that the CIP2A pathway may be a novel target for the treatment of EGFR wild-type NSCLC.

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CIP2A expression and localization in oral carcinoma and dysplasia

Cited by 46 publications

References 17 publications

Ets1 and Elk1 transcription factors regulatecancerous inhibitor of protein phosphatase 2Aexpression in cervical and endometrial carcinoma cells

Ets1 and Elk1 transcription factors regulatecancerous inhibitor of protein phosphatase 2Aexpression in cervical and endometrial carcinoma cells

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

TD-19, an Erlotinib Derivative, Induces Epidermal Growth Factor Receptor Wild-Type Nonsmall-Cell Lung Cancer Apoptosis through CIP2A-Mediated Pathway

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