Myc-dependent Purine Biosynthesis Affects Nucleolar Stress and Therapy Response in Prostate Cancer

Overview

Journal Oncotarget

Specialty Oncology

Date 2015 Apr 15

PMID 25869206

Citations 49

Authors

Stefan J Barfeld

Ladan Fazli

Margareta Persson

Lisette Marjavaara

Alfonso Urbanucci

Kirsi M Kaukoniemi

Paul S Rennie

Yvonne Ceder

Andrei Chabes

Tapio Visakorpi

Ian G Mills

Affiliations

Soon will be listed here.

Abstract

The androgen receptor is a key transcription factor contributing to the development of all stages of prostate cancer (PCa). In addition, other transcription factors have been associated with poor prognosis in PCa, amongst which c-Myc (MYC) is a well-established oncogene in many other cancers. We have previously reported that the AR promotes glycolysis and anabolic metabolism; many of these metabolic pathways are also MYC-regulated in other cancers. In this study, we report that in PCa cells de novo purine biosynthesis and the subsequent conversion to XMP is tightly regulated by MYC and independent of AR activity. We characterized two enzymes, PAICS and IMPDH2, within the pathway as PCa biomarkers in tissue samples and report increased efficacy of established anti-androgens in combination with a clinically approved IMPDH inhibitor, mycophenolic acid (MPA). Treatment with MPA led to a significant reduction in cellular guanosine triphosphate (GTP) levels accompanied by nucleolar stress and p53 stabilization. In conclusion, targeting purine biosynthesis provides an opportunity to perturb PCa metabolism and enhance tumour suppressive stress responses.

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References

Koivisto P, Kononen J, Palmberg C, Tammela T, Hyytinen E, Isola J . Androgen receptor gene amplification: a possible molecular mechanism for androgen deprivation therapy failure in prostate cancer. Cancer Res. 1997; 57(2):314-9. View

Joseph J, Lu N, Qian J, Sensintaffar J, Shao G, Brigham D . A clinically relevant androgen receptor mutation confers resistance to second-generation antiandrogens enzalutamide and ARN-509. Cancer Discov. 2013; 3(9):1020-9. DOI: 10.1158/2159-8290.CD-13-0226. View

Tilley W, Buchanan G, Hickey T, Bentel J . Mutations in the androgen receptor gene are associated with progression of human prostate cancer to androgen independence. Clin Cancer Res. 1996; 2(2):277-85. View

Culig Z, Hoffmann J, Erdel M, Eder I, Hobisch A, HITTMAIR A . Switch from antagonist to agonist of the androgen receptor bicalutamide is associated with prostate tumour progression in a new model system. Br J Cancer. 1999; 81(2):242-51. PMC: 2362859. DOI: 10.1038/sj.bjc.6690684. View

Zeller K, Zhao X, Lee C, Chiu K, Yao F, Yustein J . Global mapping of c-Myc binding sites and target gene networks in human B cells. Proc Natl Acad Sci U S A. 2006; 103(47):17834-9. PMC: 1635161. DOI: 10.1073/pnas.0604129103. View

Li S, Tong Y, Xie X, Wang Q, Zhou H, Han Y . Octameric structure of the human bifunctional enzyme PAICS in purine biosynthesis. J Mol Biol. 2007; 366(5):1603-14. DOI: 10.1016/j.jmb.2006.12.027. View

Feldman B, Feldman D . The development of androgen-independent prostate cancer. Nat Rev Cancer. 2002; 1(1):34-45. DOI: 10.1038/35094009. View

Denmeade S, Isaacs J . A history of prostate cancer treatment. Nat Rev Cancer. 2002; 2(5):389-96. PMC: 4124639. DOI: 10.1038/nrc801. View

van Dekken H, Alers J, Damen I, Vissers K, Krijtenburg P, Hoedemaeker R . Genetic evaluation of localized prostate cancer in a cohort of forty patients: gain of distal 8q discriminates between progressors and nonprogressors. Lab Invest. 2003; 83(6):789-96. DOI: 10.1097/01.lab.0000074889.76221.49. View

10.

Olson M . Sensing cellular stress: another new function for the nucleolus?. Sci STKE. 2004; 2004(224):pe10. DOI: 10.1126/stke.2242004pe10. View

11.

SWEENEY M, GERZON K, HARRIS P, HOLMES R, Poore G, Williams R . Experimental antitumor activity and preclinical toxicology of mycophenolic acid. Cancer Res. 1972; 32(9):1795-802. View

12.

Fleming W, Hamel A, MacDonald R, Ramsey E, Pettigrew N, Johnston B . Expression of the c-myc protooncogene in human prostatic carcinoma and benign prostatic hyperplasia. Cancer Res. 1986; 46(3):1535-8. View

13.

Prendergast G, Ziff E . Methylation-sensitive sequence-specific DNA binding by the c-Myc basic region. Science. 1991; 251(4990):186-9. DOI: 10.1126/science.1987636. View

14.

van der Kwast T, Schalken J, Ruizeveld de Winter J, van Vroonhoven C, Mulder E, Boersma W . Androgen receptors in endocrine-therapy-resistant human prostate cancer. Int J Cancer. 1991; 48(2):189-93. DOI: 10.1002/ijc.2910480206. View

15.

Sadi M, Walsh P, Barrack E . Immunohistochemical study of androgen receptors in metastatic prostate cancer. Comparison of receptor content and response to hormonal therapy. Cancer. 1991; 67(12):3057-64. DOI: 10.1002/1097-0142(19910615)67:12<3057::aid-cncr2820671221>3.0.co;2-s. View

16.

Amati B, Brooks M, Levy N, Littlewood T, Evan G, Land H . Oncogenic activity of the c-Myc protein requires dimerization with Max. Cell. 1993; 72(2):233-45. DOI: 10.1016/0092-8674(93)90663-b. View

17.

Jansen-Durr P, Meichle A, Steiner P, Pagano M, Finke K, Botz J . Differential modulation of cyclin gene expression by MYC. Proc Natl Acad Sci U S A. 1993; 90(8):3685-9. PMC: 46366. DOI: 10.1073/pnas.90.8.3685. View

18.

Kokontis J, Takakura K, Hay N, Liao S . Increased androgen receptor activity and altered c-myc expression in prostate cancer cells after long-term androgen deprivation. Cancer Res. 1994; 54(6):1566-73. View

19.

Grandori C, Gomez-Roman N, Felton-Edkins Z, Ngouenet C, Galloway D, Eisenman R . c-Myc binds to human ribosomal DNA and stimulates transcription of rRNA genes by RNA polymerase I. Nat Cell Biol. 2005; 7(3):311-8. DOI: 10.1038/ncb1224. View

20.

Gil J, Kerai P, Lleonart M, Bernard D, Cigudosa J, Peters G . Immortalization of primary human prostate epithelial cells by c-Myc. Cancer Res. 2005; 65(6):2179-85. DOI: 10.1158/0008-5472.CAN-03-4030. View