The long-term goals of this competing renewal are to elucidate protein kinase C (PKC) signaling mechanisms that contribute to cancer and translate these mechanistic insights into better prognostic and treatment strategies. During the current funding period, we identified PKC? as a human oncogene in non-small cell lung cancer (NSCLC), the number one cancer killer in the United States. PKC? drives anchorage-independent growth and invasion in NSCLC cells by forming a protein-protein complex with the adaptor molecule Par6. The PKC?-Par6 complex activates the Rho family GTPase Rac1 to induce expression of matrix metalloproteinase10 (MMP10). MMP10 is a critical effector of the PKC9-Par6-Rac1 signaling axis and is required for anchorage-independent growth and invasion in vitro. These mechanistic studies informed the design of a rational drug screening strategy which identified the first PKC?-targeted drug, aurothiomalate (ATM) which is currently in Phase I clinical trials for treatment of lung cancer. In this application, we will address three major aspects of oncogenic PKC? signaling. First, we will determine how PKC? activates Rac1. Preliminary data indicate that the Rac-GEF Ect2 regulates Rac1, is required for NSCLC cell transformation, associates with the oncogenic PKC?-Par6 complex and is phosphorylated by PKC?.
In Specific Aim 1 we will test the hypothesis that Ect2 is a critical effector of oncogenic PKC? and that PKC?-mediated phosphorylation regulates the oncogenic activity of Ect2. Completion of this aim will provide a novel functional link between Ect2 and PKC?. Second, we will assess whether the oncogenic PKC? signaling axis we defined in NSCLC cells in vitro is required for NSCLC tumor growth and metastasis in vivo.
In Specific Aim 2, we will test the hypothesis that the PKC?-Par6-Ect2-Rac1-MMP10 signaling axis is necessary for NSCLC tumor growth and metastasis in vivo. We will establish novel orthotopic NSCLC tumor models to assess the role of key components of this signaling axis in vivo. Third, we will determine whether MMP10 is required for lung carcinogenesis in vivo. Preliminary data demonstrate that PKC? is required for lung carcinogenesis induced by oncogenic K-ras in vivo.
In Specific Aim 3 we will test the hypothesis that MMP10 is a critical effector of PKC? in K-ras-mediated lung carcinogenesis in vivo. We will establish novel transgenic mouse models to assess whether MMP10 can drive spontaneous lung carcinogenesis, exacerbate K-ras-mediated lung carcinogenesis and/or restore K-ras-mediated lung carcinogenesis in mice lacking PKC?. Completion of these aims will provide critical new insight into oncogenic PKC? signaling, establish the role of Ect2 in NSCLC, assess the importance of oncogenic PKC? signaling in relevant preclinical NSCLC models in vivo, and determine if MMP10 is a critical mediator of lung carcinogenesis in vivo. These studies will likely reveal Ect2 and MMP10 as novel therapeutic targets for development of therapeutics for treatment of lung cancer.
Lung cancer is the number one cause of cancer death in the United States. Protein kinase C? (PKC?) is an oncogene, prognostic marker and therapeutic target in lung cancer. This project will elucidate the PKC? signaling mechanisms that drive lung cancer growth and assess the importance of PKC? signaling in lung cancer development, progression and spread in pre-clinical animal models in vivo.
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|Parker, Peter J; Justilien, Verline; Riou, Philippe et al. (2014) Atypical protein kinase Cýý as a human oncogene and therapeutic target. Biochem Pharmacol 88:1-11|
|Hill, K S; Erdogan, E; Khoor, A et al. (2014) Protein kinase C* suppresses Kras-mediated lung tumor formation through activation of a p38 MAPK-TGF* signaling axis. Oncogene 33:2134-44|
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|Greer, Yoshimi Endo; Fields, Alan P; Brown, Anthony M C et al. (2013) Atypical protein kinase C? is required for Wnt3a-dependent neurite outgrowth and binds to phosphorylated dishevelled 2. J Biol Chem 288:9438-46|
|Butler, Amanda M; Scotti Buzhardt, Michele L; Li, Shuhua et al. (2013) Protein kinase C zeta regulates human pancreatic cancer cell transformed growth and invasion through a STAT3-dependent mechanism. PLoS One 8:e72061|
|Mansfield, Aaron S; Fields, Alan P; Jatoi, Aminah et al. (2013) Phase I dose escalation study of the PKCýý inhibitor aurothiomalate for advanced non-small-cell lung cancer, ovarian cancer, and pancreatic cancer. Anticancer Drugs 24:1079-83|
|Wang, Yin; Hill, Kristen S; Fields, Alan P (2013) PKC? maintains a tumor-initiating cell phenotype that is required for ovarian tumorigenesis. Mol Cancer Res 11:1624-35|
|Justilien, Verline; Regala, Roderick P; Tseng, I-Chu et al. (2012) Matrix metalloproteinase-10 is required for lung cancer stem cell maintenance, tumor initiation and metastatic potential. PLoS One 7:e35040|
|Sajan, Mini P; Nimal, Sonali; Mastorides, Stephen et al. (2012) Correction of metabolic abnormalities in a rodent model of obesity, metabolic syndrome, and type 2 diabetes mellitus by inhibitors of hepatic protein kinase C-?. Metabolism 61:459-69|
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