Pancreatic cancer (adenocarcinoma) is the fourth leading cause of cancer deaths in the United States and carries the worst prognosis, with median life expectancy of less than a year. As the disease is diagnosed at a late stage, treatment options are limited. Surgery only modestly improves life expectancy. Pancreatic adenocarcinomas are highly refractile to conventional chemotherapies. Relative to radiation and paclitaxal, gemcitabine is recognized to be the more efficacious drug. The sobering statistic, however, is that gemcitabine only extends patient survival by several months over other therapies. The molecular basis for chemoresistance is likely to be highly complex, as combination therapies with gemcitabine have met with limited success. There is an urgent need to identify methods to enhance sensitivity of pancreatic cancer cells to chemotherapy. In preliminary experiments, we conducted a genome-wide siRNA screen to identify genes responsible for gemcitabine sensitivity. We identified a small collection of genes that include the vitamin D receptor (VDR) and various associated interacting and downstream genes. We have validated VDR to be an important determinant of gemcitabine sensitivity in vitro. Using an independent set of VDR siRNAs, gemcitabine sensitization was achieved in two cell lines (Panc1 and BXPC3) as determined by clonogenic survival. VDR is a nuclear hormone receptor that is best known for its ability to regulate genes important for calcium homeostasis and mineralization of bone. However, the activities of VDR are vast and complex as its also known for its anti-proliferative properties and is being tested in combination with cytotoxic agents for cancer treatment. We have found that VDR is required for the formation of DNA damaged foci in cells treated with DNA damaging agents. Chemosensitization of cells lacking VDR may therefore be due to disruption of DNA damage response that promote cell survival. This proposal seeks to extend the recent finding that the natural compound curcumin is a ligand for VDR. The use of curcumin as a chemosensitizer is well documented but its mode of action remains obscure. These observations combined with our preliminary data leads us to propose that curcumin acts via VDR to enhance chemosensitzation of pancreatic cancer cells. Furthermore, as the cytoprotective actions of VDR is known to depend on the context of mutant p53 status, the impact on curcumin induced chemosensitization will also be assessed. Our studies have significant clinical ramifications as a large proportion of pancreatic tumors and cell lines express mutant p53. The status of p53 may dictate whether to treat cancer patients with a vitamin D analog or antagonist and curcumin along with standard chemotherapy.

Public Health Relevance

Preliminary studies identified the vitamin D pathway to play an important role in determining response of pancreatic cancer cell lines to chemotherapy. Curcumin is a bioactive compound that exhibits chemosensitizing activity, although clinical efficacy is moderate at best. We seek to study the molecular mechanisms as to how curcumin and VDR may enhance gemcitabine cell killing as a step towards improving diagnostic and treatment strategies for pancreatic cancer patients.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Fu, Yali
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Research Institute of Fox Chase Cancer Center
United States
Zip Code
Henry, Ryan A; Kuo, Yin-Ming; Bhattacharjee, Vikram et al. (2015) Changing the selectivity of p300 by acetyl-CoA modulation of histone acetylation. ACS Chem Biol 10:146-56
Bhattacharjee, V; Zhou, Y; Yen, T J (2014) A synthetic lethal screen identifies the Vitamin D receptor as a novel gemcitabine sensitizer in pancreatic cancer cells. Cell Cycle 13:3839-56
Lal, Shruti; Burkhart, Richard A; Beeharry, Neil et al. (2014) HuR posttranscriptionally regulates WEE1: implications for the DNA damage response in pancreatic cancer cells. Cancer Res 74:1128-40
Eytan, Esther; Wang, Kexi; Miniowitz-Shemtov, Shirly et al. (2014) Disassembly of mitotic checkpoint complexes by the joint action of the AAA-ATPase TRIP13 and p31(comet). Proc Natl Acad Sci U S A 111:12019-24
Wang, Kexi; Sturt-Gillespie, Brianne; Hittle, James C et al. (2014) Thyroid hormone receptor interacting protein 13 (TRIP13) AAA-ATPase is a novel mitotic checkpoint-silencing protein. J Biol Chem 289:23928-37
Beeharry, Neil; Banina, Eugenia; Hittle, James et al. (2014) Re-purposing clinical kinase inhibitors to enhance chemosensitivity by overriding checkpoints. Cell Cycle 13:2172-91
Hu, Liang; Filippakis, Harilaos; Huang, Haomin et al. (2013) Replication stress and mitotic dysfunction in cells expressing simian virus 40 large T antigen. J Virol 87:13179-92