DigitalCommons@UNMC

Title

Unbiased analysis of pancreatic cancer radiation resistance reveals cholesterol biosynthesis as a novel target for radiosensitisation.

Authors

Joshua J. Souchek, University of Nebraska Medical CenterFollow
Michael J. Baine, University of Nebraska Medical CenterFollow
Chi Lin, University of Nebraska Medical CenterFollow
Satyanarayana Rachagani, University of Nebraska Medical CenterFollow
Suprit Gupta, University of Nebraska Medical CenterFollow
Sukhwinder Kaur, University of Nebraska Medical CenterFollow
K Lester, University of Nebraska Medical Center
D Zheng, University of Nebraska Medical CenterFollow
S Chen, University of Maryland - Baltimore
Lynette Smith, University of Nebraska Medical CenterFollow
A Lazenby, University of Nebraska Medical CenterFollow
Sonny L. Johansson, University of Nebraska Medical CenterFollow
Maneesh Jain, University of Nebraska Medical CenterFollow
Surinder K. Batra, University of Nebraska Medical CenterFollow

Document Type

Article

Journal Title

British journal of cancer

Publication Date

9-9-2014

Volume

111

Abstract

BACKGROUND: Despite its promise as a highly useful therapy for pancreatic cancer (PC), the addition of external beam radiation therapy to PC treatment has shown varying success in clinical trials. Understanding PC radioresistance and discovery of methods to sensitise PC to radiation will increase patient survival and improve quality of life. In this study, we identified PC radioresistance-associated pathways using global, unbiased techniques.

METHODS: Radioresistant cells were generated by sequential irradiation and recovery, and global genome cDNA microarray analysis was performed to identify differentially expressed genes in radiosensitive and radioresistant cells. Ingenuity pathway analysis was performed to discover cellular pathways and functions associated with differential radioresponse and identify potential small-molecule inhibitors for radiosensitisation. The expression of FDPS, one of the most differentially expressed genes, was determined in human PC tissues by IHC and the impact of its pharmacological inhibition with zoledronic acid (ZOL, Zometa) on radiosensitivity was determined by colony-forming assays. The radiosensitising effect of Zol in vivo was determined using allograft transplantation mouse model.

RESULTS: Microarray analysis indicated that 11 genes (FDPS, ACAT2, AG2, CLDN7, DHCR7, ELFN2, FASN, SC4MOL, SIX6, SLC12A2, and SQLE) were consistently associated with radioresistance in the cell lines, a majority of which are involved in cholesterol biosynthesis. We demonstrated that knockdown of farnesyl diphosphate synthase (FDPS), a branchpoint enzyme of the cholesterol synthesis pathway, radiosensitised PC cells. FDPS was significantly overexpressed in human PC tumour tissues compared with healthy pancreas samples. Also, pharmacologic inhibition of FDPS by ZOL radiosensitised PC cell lines, with a radiation enhancement ratio between 1.26 and 1.5. Further, ZOL treatment resulted in radiosensitisation of PC tumours in an allograft mouse model.

CONCLUSIONS: Unbiased pathway analysis of radioresistance allowed for the discovery of novel pathways associated with resistance to ionising radiation in PC. Specifically, our analysis indicates the importance of the cholesterol synthesis pathway in PC radioresistance. Further, a novel radiosensitiser, ZOL, showed promising results and warrants further study into the universality of these findings in PC, as well as the true potential of this drug as a clinical radiosensitiser.

MeSH Headings

Adenocarcinoma, Animals, Cell Line, Tumor, Cholesterol, DNA, Complementary, Diphosphonates, Gene Expression Profiling, Gene Knockdown Techniques, Geranyltranstransferase, Humans, Imidazoles, Immunohistochemistry, Mice, Mice, Inbred C57BL, Oligonucleotide Array Sequence Analysis, Pancreatic Neoplasms, Radiation Tolerance, Radiation-Sensitizing Agents

ISSN

1532-1827

DOI Link

10.1038/bjc.2014.385.

Creative Commons License

This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 License.

Recommended Citation

Souchek, Joshua J.; Baine, Michael J.; Lin, Chi; Rachagani, Satyanarayana; Gupta, Suprit; Kaur, Sukhwinder; Lester, K; Zheng, D; Chen, S; Smith, Lynette; Lazenby, A; Johansson, Sonny L.; Jain, Maneesh; and Batra, Surinder K., "Unbiased analysis of pancreatic cancer radiation resistance reveals cholesterol biosynthesis as a novel target for radiosensitisation." (2014). Journal Articles: Biochemistry & Molecular Biology. 77.
https://digitalcommons.unmc.edu/com_bio_articles/77