Pancreatic ductal adenocarcinoma (PDAC) is probably the most aggressive form of cancer known to date with the lowest overall 5-year survival rate. Increased growth factor signaling and K-ras mutations in PDAC lead to the generation of reactive oxygen species (ROS) at elevated rates. ROS act as second messengers in intracellular signaling cascades, which induce and maintain the oncogenic phenotype. Little is known about the protective signaling cascades that are activated by oxidative stress and regulate tumor cell survival. It is of great importance to understand these protective signaling mechanisms since their modulation may allow tipping the balance in ROS homeostasis to sensitize cancer cells to chemotherapeutics-induced cell death. It is our hypothesis that oxidative stress mediates tumor cell survival by activating Protein Kinase D. Specifically, we hypothesize that ROS-mediated PKD signaling is transmitted through the mitochondria and that PKD activated by this pathway regulates survival via the transcription factor FOXO3a. We further hypothesize that the pharmacological inhibition of PKD increases the sensitivity of tumor cells to ROS-mediated cell death. To test this we will: Determine how Protein Kinase D is recruited to the mitochondria in response to ROS (Specific Aim 1);Characterize the tumor suppressor FOXO3a as a cellular target for ROS-activated PKD (Specific Aim 2) and Characterize novel PKD inhibitors and their value for cancer therapy (Specific Aim 3). Successful completion of this proposal will contribute to the understanding of ROS- and PKD-mediated protective signaling in PDAC cells. It will show that in response to growth factors, K- ras or other inducers of ROS, as a first step in the PKD activation mechanisms, PKD is located to the mitochondria via DAG binding. It will further dissect PKD's role in tumor cell survival by identifying FOXO3a as a novel PKD target. Finally, we will characterize novel PKD-inhibiting compounds for their value in sensitizing pancreatic cancer cells to ROS- and chemotherapeutics-induced cell death. Overall our results will provide the basis for the development of novel and more potent therapeutic strategies for pancreatic cancer patients.
This proposal aims to understand a novel signaling mechanism which mediates pancreatic cancer cell survival in response to oxidative stress. We further will test if inhibiting a key enzyme in this pathway with a set of novel inhibitors will sensitize pancreatic cancer cells to chemotherapeutics.
|Yushi, Qiu; Li, Zhimin; Von Roemeling, Christina A et al. (2016) Osteopontin is a multi-faceted pro-tumorigenic driver for central nervous system lymphoma. Oncotarget 7:32156-71|
|DÃ¶ppler, Heike; Panayiotou, Richard; Reid, Elizabeth M et al. (2016) The PRKD1 promoter is a target of the KRas-NF-ÎºB pathway in pancreatic cancer. Sci Rep 6:33758|
|Liou, Geou-Yarh; DÃ¶ppler, Heike; DelGiorno, Kathleen E et al. (2016) Mutant KRas-Induced Mitochondrial Oxidative Stress in Acinar Cells Upregulates EGFR Signaling to Drive Formation of Pancreatic Precancerous Lesions. Cell Rep 14:2325-36|
|Storz, Peter (2015) Targeting protein kinase C subtypes in pancreatic cancer. Expert Rev Anticancer Ther 15:433-8|
|Liou, Geou-Yarh; DÃ¶ppler, Heike; Braun, Ursula B et al. (2015) Protein kinase D1 drives pancreatic acinar cell reprogramming and progression to intraepithelial neoplasia. Nat Commun 6:6200|
|Borges, Sahra; Perez, Edith A; Thompson, E Aubrey et al. (2015) Effective Targeting of Estrogen Receptor-Negative Breast Cancers with the Protein Kinase D Inhibitor CRT0066101. Mol Cancer Ther 14:1306-16|
|Chen, Nai-Ming; Singh, Garima; Koenig, Alexander et al. (2015) NFATc1 Links EGFR Signaling to Induction of Sox9 Transcription and Acinar-Ductal Transdifferentiation in the Pancreas. Gastroenterology 148:1024-1034.e9|
|Liou, Geou-Yarh; Storz, Peter (2015) Protein kinase D enzymes: novel kinase targets in pancreatic cancer. Expert Rev Gastroenterol Hepatol 9:1143-6|
|Liou, Geou-Yarh; Storz, Peter (2015) Detecting reactive oxygen species by immunohistochemistry. Methods Mol Biol 1292:97-104|
|Liou, Geou-Yarh; DÃ¶ppler, Heike; Necela, Brian et al. (2015) Mutant KRAS-induced expression of ICAM-1 in pancreatic acinar cells causes attraction of macrophages to expedite the formation of precancerous lesions. Cancer Discov 5:52-63|
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