Sodium butyrate induces cell death by autophagy and reactivates a tumor suppressor gene DIRAS1 in renal cell carcinoma cell line UOK146
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Sodium butyrate (SB), a histone deacetylase inhibitor, is emerging as a potent anti-cancer drug for different types of cancers. In the present study, anti-cancer activity of SB in Xp11.2 (TFE3) translocated renal cell carcinoma cell line UOK146 was studied. Anti-proliferative effect of SB in renal cell carcinoma (RCC) cell line UOK146 was evaluated by MTT assay and morphological characteristics were observed by phase contrast microscopy which displayed the cell death after SB treatment. SB induces DNA fragmentation and change in nuclear morphology observed by increased sub-G1 region cell population and nuclear blebbings. Cell cycle arrest at G2/M phase was found after SB treatment. UOK146 cell line shows autophagy mode of cell death as displayed by acridine orange staining and flow cytometry analysis. LC3-II, a protein marker of autophagy, was also found to be upregulated after SB treatment. A tumor suppressor gene DIRAS1 was upregulated after SB treatment, displaying its anti-cancer potential at molecular level. These findings suggest that SB could serve as a novel regulator of tumor suppressors and lead to the discovery of novel therapeutics with better and enhanced anti-cancer activity.
KeywordsSodium butyrate UOK146 Renal cell carcinoma Autophagy DIRAS1
We acknowledge W M Linehan, National Cancer Institute, USA, for providing the UOK146 cell line. DBT-BHU Interdisciplinary School of Life Sciences (ISLS) Banaras Hindu University, Varanasi, India, for Flow Cytometry and Real Time PCR facilities. Prof. Prasenjit Guchhait, Regional Centre for Biotechnology, Faridabad, India, for anti-LC3 antibody. The Indian Council of Medical Research (ICMR), Government of India, New Delhi, for fellowship support of JRF and SRF to Shiv Prakash Verma.
Compliance with ethical standards
The authors declare that they have no competing interests.
- Abramova MV, Pospelova TV, Nikulenkov FP, Hollander CM, Fornace AJ Jr, Pospelov VA (2006) G1/S arrest induced by histone deacetylase inhibitor sodium butyrate in E1A + Ras-transformed cells is mediated through down-regulation of E2F activity and stabilization of beta-catenin. J Biol Chem 281:21040–21051CrossRefPubMedGoogle Scholar
- Bergom C, Hauser AD, Rymaszewski A, Gonyo P, Prokop JW, Jennings BC, Lawton AJ, Frei A, Lorimer EL, Aguilera-Barrantes I, Mackinnon AC, Noon K, Fierke CA, Williams CL (2016) The tumor-suppressive small GTPase DiRas1 binds the noncanonical guanine nucleotide exchange factor SmgGDS and antagonizes SmgGDS interactions with oncogenic small GTPases. J Biol Chem 291:6534–6545CrossRefPubMedPubMedCentralGoogle Scholar
- Dos Santos MP, de Farias CB, Roesler R, Brunetto AL, Abujamra AL (2014) In vitro antitumor effect of sodium butyrate and zoledronic acid combined with traditional chemotherapeutic drugs: a paradigm of synergistic molecular targeting in the treatment of Ewing sarcoma. Oncol Rep 31:955–968CrossRefPubMedGoogle Scholar
- Elizabeth A, Williams Jonathan M, Coxhead and John C Mathers (2003) Anti-cancer effects of butyrate: use of microarray technologies to investigate mechanisms. Proc Nutr Soc 62:107–115Google Scholar
- Ogawa H, Rafiee P, Fisher PJ, Johnson NA, Otterson MF, Binion DG, Ogawa H, Rafiee P, Fisher PJ, Johnson NA, Otterson MF, Binion DG (2003) Sodium butyrate inhibits angiogenesis of human intestinal microvascular endothelial cells through COX-2 inhibition. FEBS Lett 554:88–94CrossRefPubMedGoogle Scholar
- Parikh J, Coleman T, Messias N, Brown J (2009) Temsirolimus in the treatment of renal cell carcinoma associated with Xp11.2 translocation/TFE gene fusion proteins: a case report and review of literature. Rare Tumors 1:e53Google Scholar
- Sidhar SK, Clark J, Gill S, Hamoudi R, Crew AJ, Gwilliam R, Ross M, Linehan WM, Birdsall S, Shipley J, Cooper CS (1996) The t(X;1)(p11.2;q21.2) translocation in papillary renal cell carcinoma fuses a novel gene PRCC to the TFE3 transcription factor gene. Hum Mol Genet 5:1333–1338CrossRefPubMedGoogle Scholar
- Sutton MN, Lu Z, Bast RC Jr. (2016) DIRAS1 and DIRAS2 are tumor suppressor candidates that inhibit cell growth, motility, and proliferation while regulating autophagy in ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17–20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res. 22(2 Suppl):Abstract nr A43Google Scholar