Radiosensitizing effects of Sestrin2 in PC3 prostate cancer cells

Document Type: Original Article


1 Department of Urology, Affiliated Nanhua Hospital of University of South China, 336 South Dongfeng Road, Hengyang, 421002, Hunan Province, China

2 Department of Obstetrics and Gynaecology, Affiliated Nanhua Hospital of University of South China, 336 South Dongfeng Road, Hengyang, 421002, Hunan Province, China

3 Pathophysiology Department, University of South China, Hengyang City, Hunan Province, PRC,421001

4 Emergency Department, The Second Affiliated Hospital, University of South China, Hengyang City, Hunan Province, PRC,421001


Objective(s): The stress-responsive genes of Sestrin family are recognized as new tumor suppressor genes in breast carcinoma, however, the function of Sestrin family in human prostate cancer is not clear. Ionizing radiation (IR) is known to induce Sestrin gene expression in breast cancer cells. However, the response of Sestrin to IR has not been reported in PC3 prostate cancer cells.
Materials and Methods: Sestrin2 expression in prostate cancer cell lines (PC3, LNCaP clone FGC, and DU145) was detected by Western blot and real-time PCR. Cell counting kit (CCK-8) was used to detect cellular proliferation. The radiosensitivity of PC3 cells was detected by clonogenic assay.
Results: Sestrin2 expression in prostate cancer cell lines (PC3, LNCaP clone FGC, and DU145) is low. In vitro assays indicated that over-expressing Sestrin2 in human prostate cancer PC3 inhibited tumor proliferation. In addition, elevated Sestrin2 expression sensitized PC3 cells to IR.
Conclusion: We determined Sestrin2 may function as a tumor suppressor through repressing proliferation, mediating sensitization to IR in PC3 cells.


Main Subjects

1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA: CA Cancer J Clin 2011;61:69-90.
2. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010;127:2893-917.
3. Hu Y, Zhao Q, Rao J, Deng H, Yuan H, Xu B. Longitudinal trends in prostate cancer incidence, mortality, and survival of patients from two Shanghai city districts: a retrospective population-based cohort study, 2000-2009. BMC public health. 2014;14:356.
4. Killock D. Prostate cancer: viral gene therapy can improve IMRT. Nat Rev Urol 2014;11:362.
5. Fenner A. Prostate cancer: optimizing active surveillance: patient and protocol. Nat Rev Urol 2014;11:362.
6. Lee JH, Budanov AV, Karin M. Sestrins orchestrate cellular metabolism to attenuate aging. Cell Metab2013;18:792-801.
7. Budanov AV, Sablina AA, Feinstein E, Koonin EV, Chumakov PM. Regeneration of peroxiredoxins by p53-regulated sestrins, homologs of bacterial AhpD. Science 2004;304:596-600.
8. Bae SH, Sung SH, Oh SY, Lim JM, Lee SK, Park YN, et al. Sestrins activate Nrf2 by promoting p62-dependent autophagic degradation of Keap1 and prevent oxidative liver damage. Cell Metab2013;17:73-84.
9. Lee JH, Budanov AV, Talukdar S, Park EJ, Park HL, Park HW, et al. Maintenance of metabolic homeostasis by Sestrin2 and Sestrin3. Cell Metab2012;16:311-321.
10. Budanov AV, Karin M. p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling. Cell 2008;134:451-460.
11. Bristow RG, Hill RP. Hypoxia and metabolism. Hypoxia, DNA repair and genetic instability. Nat Rev Cancer2008;8:180-192.
12. Sanli T, Linher-Melville K, Tsakiridis T, Singh G. Sestrin2 modulates AMPK subunit expression and its response to ionizing radiation in breast cancer cells. PLoS One 2012;7:e32035.
13. Braunstein S, Badura ML, Xi Q, Formenti SC, Schneider RJ. Regulation of protein synthesis by ionizing radiation. Mol Cell Biol 2009;29:5645-5656.
14. Qu SL, Fan WJ, Zhang C, Guo F, Pan WJ, Han D, et al. Mipu1 inhibits lipid accumulation through down-regulation of CD36 in RAW264.7 cells. Cell Physiol Biochem 2015;37:879-889.
15. Qu SL, Fan WJ, Zhang C, Guo F, Han D, Pan WJ, et al. Mipu1 overexpression protects macrophages from oxLDL-induced foam cell formation and cell apoptosis. DNA Cell Biol 2014;33:839-846.
16. Budanov AV. Stress-responsive sestrins link p53 with redox regulation and mammalian target of rapamycin signaling. Antioxid Redox Signal 2011;15:1679-1690.
17. Lee JH, Budanov AV, Park EJ, Birse R, Kim TE, Perkins GA, et al. Sestrin as a feedback inhibitor of TOR that prevents age-related pathologies. Science 2010;327:1223-1228.
18. Maiuri MC, Malik SA, Morselli E, Kepp O, Criollo A, Mouchel PL, et al. Stimulation of autophagy by the p53 target gene Sestrin2. Cell Cycle 2009;8:1571-1576.
19. Sablina AA, Budanov AV, Ilyinskaya GV, Agapova LS, Kravchenko JE, Chumakov PM. The antioxidant function of the p53 tumor suppressor. Nat Med 2005;11:1306-1313.
20. Zhao B, Shah P, Budanov AV, Qiang L, Ming M, Aplin A, et al. Sestrin2 protein positively regulates AKT enzyme signaling and survival in human squamous cell carcinoma and melanoma cells. J Biol Chem 2014;289:35806-35814.
21. Byun JK, Choi YK, Kim JH, Jeong JY, Jeon HJ, Kim MK, et al. A Positive Feedback Loop between Sestrin2 and mTORC2 Is Required for the Survival of Glutamine-Depleted Lung Cancer Cells. Cell Rep 2017;20:586-599.
22. Hu J, Lei H, Fei X, Liang S, Xu H, Qin D, et al. NES1/KLK10 gene represses proliferation, enhances apoptosis and down-regulates glucose metabolism of PC3 prostate cancer cells. Sci Rep 2015;5:17426.
23. Peng X, Li W, Yuan L, Mehta RG, Kopelovich L, McCormick DL. Inhibition of proliferation and induction of autophagy by atorvastatin in PC3 prostate cancer cells correlate with downregulation of Bcl2 and upregulation of miR-182 and p21. PLoS One 2013;8:e70442.