Our long-term goals are to elucidate protein kinase C (PKC) signaling mechanisms that contribute to cancer and translate these mechanistic insights into better prognostic and treatment strategies. In previous funding periods, we discovered that PKC? is an oncogene in non-small cell lung cancer (NSCLC) the leading cause of cancer death in the United States, elucidated a major oncogenic PKC? signaling pathway, and developed a therapeutic agent that targets oncogenic PKC? signaling that is currently being evaluated in the clinic. During the current funding period we showed that: 1) PKC? forms an oncogenic PKC?/Par6 signaling complex in the cytoplasm of NSCLC cells that is necessary for cell proliferation and invasion in vitro, and tumor formation in vivo;2) the guanine nucleotide exchange factor (GEF) Ect2 binds the PKC?/Par6 complex and activates Rac1, a key downstream effector of this complex;3) PKC? regulates the intracellular location and oncogenic activity of Ect2 through direct binding and phosphorylation;4) matrix metalloproteinase 10 (Mmp10) is a critical downstream effector of the PKC?/Ect2/Par6/Rac1 signaling axis that is required for NSCLC cell proliferation and invasion in vitro, and Kras-mediated lung tumorigenesis in vivo;and 5) both PKC? and Mmp10 are required for Kras-mediated transformation of bronchio-alveolar stem cells (BASCs), putative lung tumorinitiating cells (TICs) in vivo. Our preliminary studies indicate that: 1) the PKC?/Ect2/Par6/Rac1/Mmp10 signaling axis maintains a tumor-initiating cell phenotype in NSCLC cells characterized by stem-like behavior and enhanced tumorigenicity;2) a significant pool of cellular Ect2 localizes to the nucleolus in a PKC?- dependent manner where it regulates ribosomal RNA (rRNA) transcription;3) PKC? transcriptionally activates cell autonomous hedgehog (Hh) signaling in NSCLC tumor-initiating cells;and 4) PKC? regulates recruitment of the stem cell pluripotency factor Sox2 to th promoter region of the gene encoding Hedgehog Acyl Transferase (HHAT), an enzyme that catalyzes a key step in the production of Hh ligand. Based on these data, we hypothesize that: 1) PKC?-mediated transformation involves regulation of Ect2 nucleolar localization and pre-ribosomal RNA synthesis;2) Ect2 signaling is required for Kras-mediated BASC transformation and lung tumorigenesis in vivo;3) PKC? maintains a lung tumor-initiating cell phenotype, at least in part, through Sox2-mediated induction of HHAT transcription and activation of a cell autonomous Hh signaling axis;and 4) HHAT, a PKC?-dependent transcriptional target, plays a key role in lung tumor-initiating activity in vivo. These hypotheses will be tested through completion of four interrelated specific aims to: 1) determine the mechanism by which PKC? and Ect2 regulate ribosomal RNA transcription;2) assess the role of Ect2 in Kras-mediated lung tumorigenesis;3) determine the mechanism by which PKC? regulates hedgehog acyl-transferase (HHAT) expression;and 4) assess the role of HHAT in lung tumorigenesis.

Public Health Relevance

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 novel PKC? signaling mechanisms that drive lung cancer growth, assess the importance of PKC? signaling in lung cancer development, progression and spread in pre-clinical animal models in vivo, and determine the translational relevance of these findings to primary human lung cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA081436-17
Application #
8703614
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Watson, Joanna M
Project Start
1999-04-02
Project End
2018-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
17
Fiscal Year
2014
Total Cost
$379,513
Indirect Cost
$137,013
Name
Mayo Clinic Jacksonville
Department
Type
DUNS #
153223151
City
Jacksonville
State
FL
Country
United States
Zip Code
32224
Wang, Y; Justilien, V; Brennan, K I et al. (2016) PKCι regulates nuclear YAP1 localization and ovarian cancer tumorigenesis. Oncogene :
Ali, Syed A; Justilien, Verline; Jamieson, Lee et al. (2016) Protein Kinase Cι Drives a NOTCH3-dependent Stem-like Phenotype in Mutant KRAS Lung Adenocarcinoma. Cancer Cell 29:367-78
Fields, Alan P; Justilien, Verline; Murray, Nicole R (2016) The chromosome 3q26 OncCassette: A multigenic driver of human cancer. Adv Biol Regul 60:47-63
Liou, Geou-Yarh; Döppler, Heike; Braun, Ursula B et al. (2015) Protein kinase D1 drives pancreatic acinar cell reprogramming and progression to intraepithelial neoplasia. Nat Commun 6:6200
Jatoi, Aminah; Radecki Breitkopf, Carmen; Foster, Nathan R et al. (2015) A mixed-methods feasibility trial of protein kinase C iota inhibition with auranofin in asymptomatic ovarian cancer patients. Oncology 88:208-13
Justilien, Verline; Fields, Alan P (2015) Molecular pathways: novel approaches for improved therapeutic targeting of Hedgehog signaling in cancer stem cells. Clin Cancer Res 21:505-13
Butler, Amanda M; Scotti Buzhardt, Michele L; Erdogan, Eda et al. (2015) A small molecule inhibitor of atypical protein kinase C signaling inhibits pancreatic cancer cell transformed growth and invasion. Oncotarget 6:15297-310
Parker, Peter J; Justilien, Verline; Riou, Philippe et al. (2014) Atypical protein kinase Cι as a human oncogene and therapeutic target. Biochem Pharmacol 88:1-11
Justilien, Verline; Walsh, Michael P; Ali, Syed A et al. (2014) The PRKCI and SOX2 oncogenes are coamplified and cooperate to activate Hedgehog signaling in lung squamous cell carcinoma. Cancer Cell 25:139-51
Hill, K S; Erdogan, E; Khoor, A et al. (2014) Protein kinase Cα suppresses Kras-mediated lung tumor formation through activation of a p38 MAPK-TGFβ signaling axis. Oncogene 33:2134-44

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