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Entity | Various cancers |
Note | PKCι overexpression has been observed in numerous human cancers including cancers of the lung (Regala et al., 2005b), pancreas (Scotti et al., 2010), stomach (Takagawa et al., 2010), colon (Murray et al., 2004), esophagus (Yang et al., 2008), liver (Du et al., 2009), bile duct (Li et al., 2008), breast (Kojima et al., 2008), ovary (Weichert et al., 2003; Eder et al., 2005; Zhang et al., 2006), prostate (Ishiguro et al., 2009), and brain (Patel et al., 2008). PKCι is itself an oncogene, which appears to be activated through tumor-specific overexpression. In addition, however, PKCι is activated downstream of other oncogenes including oncogenic Ras, Bcr-Abl and Src. |
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Entity | Non Small Cell Lung Cancer (NSCLC) |
Prognosis | Elevated levels of PKCι expression correlate with poor clinical outcome in NSCLC patients (Regala et al., 2005b). |
Cytogenetics | The PRKCI gene is amplified as part of the 3q26 amplicon in NSCLC. |
Oncogenesis | PKCι is an oncogene in NSCLC. PRKCI is amplified as part of the 3q26 amplicon in NSCLC and amplication drives PKCι overexpression in NSCLC cell lines and primary NSCLC tumours. PKCι is required for transformed (anchorage-independent) growth and invasion of human NSCLC cells (Frederick et al., 2008; Regala et al., 2005a). Disruption of the Prkci gene inhibits oncogenic Kras induced expansion and transformation of tumor-initiating, lung stem-like cells. Consequently, genetic loss of Prkci dramatically inhibits Kras-initiated hyperplasia and subsequent lung tumor formation in vivo. PKCι enhances resistance of NSCLC to NNK-induced apoptosis by phosphorylating the pro-apoptotic protein BAD (Jin et al., 2005). PKCι forms an oncogeneic complex with Par6 that activates a Rac1-Mek-Erk signaling axis that drives the transformed growth and invasion of NSCLC cells in vitro (Frederick et al., 2008; Regala et al., 2005a) and tumorigenicity in vivo (Regala et al., 2005a). PKCι and the oncogene ECT2 are genetically linked through coordinate gene amplification as part of the 3q26 amplicon in NSCLC tumors (Justilien and Fields, 2009). PKCι phosphorylates Ect2 and forms an oncogenic PKCι-Par6-Ect2 complex that drives NSCLC cell transformation by activating Rac1 (Justilien and Fields, 2009; Justilien et al., 2011). Expression of MMP10 is regulated through the PKCι-Par6-Rac1 signaling axis and MMP10 represents a key downstream effector in PKCι mediated transformation in lung cancer cells that is required for transformed growth and invasion (Frederick et al., 2008). PKCι also regulates expression of COPB2, ELF3, RFC4, and PLS1 in primary lung adenocarcinoma (Erdogan et al., 2009). The PKCι inhibitor aurothiomalate (ATM) disrupts the PB1-PB1 domain interaction between PKCι and Par6 and inhibits PKCι-mediated Rac1 activation and blocks anchorage-independent growth of NSCLC cells in vitro and tumorigenicity in vivo (Erdogan et al., 2006; Stallings-Mann, 2006). |
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Entity | Colon cancer |
Oncogenesis | PKCι expression is elevated in human colon tumors, AOM-induced colon tumors in mice (Murray et al., 2004) and intestinal tumors in APCMin/+ mice (Murray et al., 2009; Oster and Leitges, 2006). Expression of caPKCι in the colonic epithelium of mice led to an increase in the number of AOM-induced colon tumors, and promoted tumor progression from benign adenoma to malignant intramucosal carcinoma (Murray et al., 2004) PKCι is required for oncogenic Ras-mediated transformation of the intestinal epithelium in vitro and in vivo. PKCι is also required for the formation of intestinal tumors in APCMin/+ mice (Murray et al., 2009). |
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Entity | Pancreatic cancer |
Prognosis | PKCι overexpression predicts poor survival in pancreatic cancer patients (Scotti et al., 2010). |
Oncogenesis | PKCι is significantly overexpressed in human pancreatic cancer. Knock down of PKCι expression using lentiviral-mediated shRNA blocked transformed (anchorage-independent) growth and invasion of human Pancreatic Ductal Adenocarcinoma (PDAC) cells (Scotti et al., 2010). Disruption of PKCι expression also blocks tumorigenicity of PDAC cell tumors injected orthotopically into the pancreas (Scotti et al., 2010). Analysis of human PDAC cells after orthotopic injection into the mouse pancreas revealed that PKCι-deficient tumor cells yielded significantly smaller tumors and significantly fewer metastases to the kidney, liver, diaphragm and mesentery (Scotti et al., 2010). The Rac1-MEK/ERK1/2 signaling axis is required for PKCiota-mediated transformed growth and cellular invasion of PDAC cells (Scotti et al., 2010). |
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Entity | Ovarian cancer |
Prognosis | PKCι expression is a strong predictor of survival when combined in a multi-variate analysis with tumor cyclin E expression (Eder et al., 2005). |
Cytogenetics | The PRKCI gene is amplified as part of the 3q26 amplicon in ovarian cancer (Eder et al., 2005). |
Oncogenesis | PKCι is frequently overexpressed in patients with ovarian cancer (Eder et al., 2005; Weichert et al., 2003; Zhang et al., 2006). PKCι expression in ovarian cancer patients correlates with tumor stage suggesting the involvement of PKCι in tumor progression and aggressiveness (Eder et al., 2005; Weichert et al., 2003; Zhang et al., 2006). Decreased PKCι expression reduced anchorage-independent growth of ovarian cancer cells, whereas overexpression of PKCι promoted murine ovarian surface epithelium transformation (Zhang et al., 2006). |
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Entity | Chronic myelogenous leukemia |
Oncogenesis | PKCι is highly expressed in human K562 leukemia cells and functions as a survival gene in chronic myelogenous leukemia (CML). The chimeric tyrosine kinase oncogene Bcr-Abl activates a Ras/Mek/Erk signaling pathway that stimulates PKCι expression through an Elk1 transcription factor site in the proximal promoter of PKCι (Gustafson et al., 2004). Bcr-Abl activation of PKCι is necessary and sufficient to mediate apoptotic resistance to chemotherapy in K562 CML cells (Murray and Fields, 1997). |
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Entity | Gliomas |
Oncogenesis | PKCι is overexpressed in glioblastoma multiforme. PKCι is required for survival and chemoresistance of glioblastoma cells. Genetic disruption of PKCι expression results in sensitization of glioblastoma cells to cisplatin (Baldwin et al., 2008). RNAi mediated depletion of PKCι also blocks the proliferative and invasive properties of glioma cell lines in vitro (Baldwin et al., 2008; Patel et al., 2008). PKCι promotes survival in glioblastoma cells through attenuation of p38 mitogen-activated protein kinase signaling that protects these cells against cytotoxicity to chemotherapeutic agents (Baldwin et al., 2008). |
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Entity | Esophageal cancer |
Cytogenetics | PRKCI gene is amplified as part of the 3q26 amplicon (Yang et al., 2008). |
Oncogenesis | PRKCI is amplified in 53% of esophageal squamous cell carcinomas (ESCC) and PKCι protein expression correlated with PRKCI gene amplification in these tumors (Yang et al., 2008). Examination of clinicopathologic features of ESCC tumors revealed a significant correlation between PRKCI expression and larger tumor size, later stage and lymph node metastasis suggesting that PRKCI overexpression is a hallmark of tumor progression and metastasis in ESCC (Yang et al., 2008). |
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