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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA140182-05
Application #
8598858
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Salnikow, Konstantin
Project Start
2010-03-01
Project End
2014-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
5
Fiscal Year
2014
Total Cost
$277,156
Indirect Cost
$96,008
Name
Mayo Clinic Jacksonville
Department
Type
DUNS #
153223151
City
Jacksonville
State
FL
Country
United States
Zip Code
32224
Liou, Geou-Yarh; Döppler, 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
Zheng, Hanqiu; Shen, Minhong; Zha, Yin-Lian et al. (2014) PKD1 phosphorylation-dependent degradation of SNAIL by SCF-FBXO11 regulates epithelial-mesenchymal transition and metastasis. Cancer Cell 26:358-73
Döppler, Heike; Bastea, Ligia I; Borges, Sahra et al. (2014) Protein kinase d isoforms differentially modulate cofilin-driven directed cell migration. PLoS One 9:e98090
Borges, Sahra; Storz, Peter (2013) Protein kinase D isoforms: new targets for therapy in invasive breast cancers? Expert Rev Anticancer Ther 13:895-8
Doppler, Heike R; Bastea, Ligia I; Lewis-Tuffin, Laura J et al. (2013) Protein kinase D1-mediated phosphorylations regulate vasodilator-stimulated phosphoprotein (VASP) localization and cell migration. J Biol Chem 288:24382-93
Doppler, Heike; Bastea, Ligia I; Eiseler, Tim et al. (2013) Neuregulin mediates F-actin-driven cell migration through inhibition of protein kinase D1 via Rac1 protein. J Biol Chem 288:455-65
Borges, Sahra; Doppler, Heike; Perez, Edith A et al. (2013) Pharmacologic reversion of epigenetic silencing of the PRKD1 promoter blocks breast tumor cell invasion and metastasis. Breast Cancer Res 15:R66
Döppler, Heike; Liou, Geou-Yarh; Storz, Peter (2013) Downregulation of TRAF2 mediates NIK-induced pancreatic cancer cell proliferation and tumorigenicity. PLoS One 8:e53676
Storz, Peter (2013) Targeting the alternative NF-?B pathway in pancreatic cancer: a new direction for therapy? Expert Rev Anticancer Ther 13:501-4
Bastea, Ligia I; Doppler, Heike; Pearce, Sarah E et al. (2013) Protein kinase D-mediated phosphorylation at Ser99 regulates localization of p21-activated kinase 4. Biochem J 455:251-60

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