MicroRNA-29a plays a prominent role in PRIMA-1Met-induced apoptosis in ovarian cancer cells


  • Nilüfer Gülmen İmir 1. Department of Biology Education, Faculty of Education, University of Akdeniz, Antalya; 2. Department of Biology, Life Sciences Institute, University of Akdeniz, Antalya http://orcid.org/0000-0002-5508-8666


apoptosis, miRNA29a, ovarian cancer, PRIMA-1Met


Paper description:

  • This study investigates whether miRNA-29a has a potential role in PRIMA-1Met-induced apoptosis.
  • Cell viability, apoptosis and miRNA-29a expression were examined by MTS, FACS analysis, and by RT-qPCR, respectively, in human ovarian cancer (Caov-3 (mutant p53)) and A2780 (wild-type p53) cells.
  • The antitumor activity of PRIMA-1Met was independent of p53 in ovarian cancer cells, it induced apoptosis by increasing miRNA-29a.
  • These results provide a basis for further studies aimed at elucidating the mechanism of Prima-1Met-induced apoptosis.

Abstract: The structural analog of the small 2,2-bis(hydroxymethyl)-1-azabicyclo[2,2,2]octan-3-one molecule named PRIMA-1Metfor “p53 reactivation and induction of massive apoptosis” has been shown to inhibit cell growth and induce apoptosis in human tumor cells by restoring the tumor suppressor function of tumor protein p53. In several microRNA (miRNA) profiling studies related to ovarian cancer, different miRNAs associated with PRIMA-1Met have been reported, but miRNAs related to PRIMA-1Met-induced apoptosis remain unclear. This study was designed to explain the potential mechanism of PRIMA-1-induced apoptosis. According to the MTSassay and fluorescence-activated cell sorting (FACS) analysis results, PRIMA-1Met induced a significant decrease in cell viability and an increase in apoptosis in both A2780 and Caov-3 cells, regardless of p53 status. PRIMA-1Met upregulated miRNA-29a in both cell lines. To determine the effect of miRNA-29a on PRIMA-1Met-induced apoptosis, A2780 and Caov-3 cells were transfected with miRNA-29a inhibitor. After treatment with PRIMA-1Met, cell viability increased and apoptosis decreased in the transfected cells. The results of this study suggest that miRNA-29a potentially regulates PRIMA-1Met-induced apoptosis in ovarian cancer cells.


Received: November 28, 2019;Revised: February 12, 2020;Accepted: March 10, 2020; Published online: March 18, 2020

How to cite this article: İmir NG. MicroRNA-29a plays a prominent role in PRIMA-1Met-induced apoptosis in ovarian cancer cells. Arch Biol Sci. 2020;72(2):173-9.


Download data is not yet available.


Harris CC. Structure and function of the p53 tumor suppressor gene: Clues for rational cancer therapeuetic strategies. J Natl Cancer Inst. 1996;88(20):1442-55.

Sullivan KD, Galbraith MD, Andrysik Z, Espinosa JM. Mechanisms of transcriptional regulation by p53. Cell Death Differ.2018;25:133-43.

Teneriello MG, Ebina M, Linnoila R, Henry M, Nash JD, Park RC, Birrer MJ. p53 and Ki-ras gene mutations in epithelial ovarian neoplasms. Cancer Res. 1993;53:3103-08.

Mazare R, Pujol P, Maudelonde T, Jeanteur P, Theillet C. p53 mutations in ovarian cancer: a late event? Oncogene. 1991;6:1685-90.

Eccles DM, Brett L, Lessells A, Gruber L, Lane D, Steel CM, Leonard RC. Overexpression of the p53 protein and allele loss at 17p13 in ovarian carcinoma. Br J Cancer. 1992;65:40-4.

Kohler MF, Kerns BJ, Humphrey PA, Marks JR, Bast RC, Berchuck A. Mutation and overexpression of p53 in earlystage epithelial ovarian cancer. Obstet Gynecol. 1993;81:643-50.

Wang Z and Sun Y. Targeting p53 for novel anticancer therapy. Transl Oncol. 2010;3(1):1-12.

Hoe KK, Verma CS, Lane DP. Drugging the p53 pathway: understanding the route to clinical efficacy. Nat Rev Drug Discov. 2014;13:217-36.

Duffy MJ, Synnott NC, McGowan PM, Crown J, McGowan PM, Crown J, O'Connor D, Gallagher WM. p53 as a target for the treatment of cancer. Cancer Treat Rev. 2014;40(10):1153-60.

Bykov VJ, Issaeva N, Shilov A, Hultcrantz M, Pugacheva E, Chumakov P, Bergman J, Wiman KG, Selinova G. Restoration of the tumor suppressor function to mutant p53 by a low molecular-weight compound. Nat Med. 2002;8:282-8.

Selinova G, Wiman KG. Reactivation of mutant p53: molecular mechanisms and therapeutic potential. Oncogene. 2007;26(15):2243-54.

Bykov VJ, Zache N, Stridh H, Westman J, Bergman J, Selivanova G, Wiman KG. PRIMA-1MET synergizes with cisplatin to induce tumor cell apoptosis. Oncogene. 2005;24:3484-91.

Shi H, Lambert JM, Hautefeuille A, Bykov VJ, Wiman KG, Hainaut P, Caron de Fromentel C. In vitro and in vivo cytotoxic effects of PRIMA-1 on hepatocellular carcinoma cells expressing mutant p53ser249. Carcinogenesis. 2008;29:1428-34.

Zache N, Lambert JM, Wiman KG, Bykov VJ. PRIMA-1MET inhibits growth of mouse tumors carrying mutant p53. Cell Oncol. 2008;30:411-8.

Liang Y, Besch-Williford C, Hyder SM. PRIMA-1 inhibits growth of breast cancer cells by re-activating mutant p53 protein. Int J Oncol. 2009;35:1015-23.

Zandi R, Selivanova G, Christensen CL, Gerds TA, Willumsen BM, Poulsen HS. PRIMA-1Met/APR-246 induces apoptosis and tumor growth delay in small cell lung cancer expressing mutant p53. Clin Cancer Res. 2011;17:2830-41.

Oliveto S, Mancino M, Manfrini N, Biffo S. Role of microRNAs in translation regulation and cancer. World J Biol Chem. 2017;8(1):45-56.

Zhang B, Pan X, Cobb GP, Anderson TA. MicroRNAs as oncogenes and tumor suppressors. Dev Biol. 2007;302:1-12.

Kumar MS, Lu J, Mercer KL, Golub TR, Jacks T. Impaired microRNA processing enhances cellular transformation and tumorigenesis. Nat Genet. 2007;39:673-7.

Yang D, Sun Y, Hu L, Zheng H, Ji P, Zhao Y, Reynolds S, Cheng H, Rupaimoole R, Cogdell D, Nykter M, Broaddus R, Rodriguez-Aguayo C, Lopez-Berestein G, Liu J, Shmulevich I, Sood AK, Chen K, Zhang W. Intregrated analyses identify a master microRNA regulatory network for the mesenchymal subtype in serous ovarian cancer. Cancer Cell. 2013;23:186-99.

Iorio MV, Visone R, Di Leva G, Donati V, Petrocca F, Casalini P, Taccioli C, Volinia S, Liu CG, Alder H, Calin GA, Menard S, Croce CM. MicroRNA signatures in human ovarian cancer. Cancer Res. 2007;67:8699-707.

Yang N, Kaur S, Volinia S, Greshock J, Lassus H, Hasegawa K, Liang S, Leminen A, Deng S, Smith L, Johnstone CN, Chen XM, Liu CG, Huang Q, Katsaros D, Calin GA, Weber BL, Bützow R, Croce CM, Coukos G, Zhang L. MicroRNA microarray identifies Let-7i as a novel biomarker anti-therapeutic target in human epithelial ovarian cancer. Cancer Res. 2008;68:10307-14.

Dahiya N, Sherman-Baust CA, Wang TL, Davidson B, Shih IM, Zhang Y, Wood W, Becker KG, Morin PJ. MicroRNA expression and identification of putative miRNA targets in ovarian cancer. PLoS One. 2008;3(6):e2436.

Nam EJ, Yoon H, Kim SW, Kim H, Kim YT, Kim JH, Kim JW, Kim S. MicroRNA expression profiles in serous ovarian carcinoma. Clin Cancer Res. 2008;14:2690-95.

Dahiya N and Morin PJ. MicroRNAs in ovarian carcinomas. Endocr Relat Cancer. 2010;17:77-89.

Mateescu B, Batista L, Cardon M, Gruosso T, de Feraudy Yi Mariani O, Nicolas A, Meyniel JP, Cottu P, Sastre-Garau X, Mechta-Grigoriou F. miR-141 and miR-200a act on ovarian tumorigenesis by controlling oxidative stress response. Nat Med. 2011;17:1627-35.

Yeh YM, Chuang CM, Chao KC, Wang LH. MicroRNA-138 suppresses ovarian cancer cell invasion and metastasis by targeting SOX4 and HIF-1a. Int J Cancer. 2013;133:867-78.

Park SY, Lee JH, Ha M, Nam JW, Kim VN. miR-29 miRNAs activate p53 by targeting p85 alpha and CDC42. Nat Struct Mol Biol. 2009;16(1):23-9.

Aydemir EA, Oz ES, Gokturk RS, Ozkan G, Fiskin K. Glycyrrhizaflavescens subsp. antalyensis exerts antiproliferative effects on melanoma cells via altering TNF-α and IFN-α levels. Food Chem Toxicol. 2011;49(4):820-8.

Livak KJ and Schmittgen TD. Analysis of relative gene expres¬sion data using real time quantitative PCR and the 2( delta delta C(T)) method. Methods. 2001;25:402 8.

Parrales A and Iwakuma T. Targeting oncogenic mutant p53 for cancer therapy. Front Oncol. 2015;5:288.

Bykov VJ, Issaeva N, Selivanova G, Wiman KG. Mutant p53-dependent growth suppression distinguishes PRIMA-1 from known anticancer drugs: a statistical analysis of information in the National Cancer Institute database. Carcinogenesis. 2002;23:2011-8.

Izetti P, Hautefeuille A, Abujamra AL, de Farias CB, Giacomazzi J, Alemar B, Lenz G, Roesler R, Schwartsmann G, Osvaldt AB, Hainaut P, Ashton-Prolla P. PRIMA-1, a mutant p53 reactivator, induces apoptosis and enhances chemotherapeutic cytotoxicity in pancreatic cancer cell lines. Invest New Drugs. 2014;32:783-94.

Russo D, Ottaggio L, Foggetti G, Masini M, Masiello P, Fronza G, Menichini P. PRIMA-1 induces autophagy in cancer cells carrying mutant or wild type p53. BiochimBiophysActa. 2013;1833:1904-13.

Aryee DN, Niedan S, Ban J, Schwentner R, Muehlbacher K, Kauer M, Kofler R, Kovar H. Variability in functional p53 reactivation by PRIMA-1(Met)/APR-246 in Ewing sarcoma. Br J Cancer. 2013;109:2696-704.

Tessoulin B, Descamps G, Moreau P, Maïga S, Lodé L, Godon C, Marionneau-Lambot S, Oullier T, Le Gouill S, Amiot M, Pellat-Deceunynck C. PRIMA-1Met induces myeloma cell death independent of p53 by impairing the GSH/ROS balance. Blood. 2014;124:1626-36.

Li XL, Zhou J, Chan ZL, Chooi JYi Chen ZR, Chang WJ. PRIMA-1met (APR-246) inhibits growth of colorectal cancer cells with different p53 status through distinct mechanisms. Oncotarget. 2015;6(34):36689-99.

Yoshikawa N, Kajiyama H, Nakamura K, Utsumi F, Niimi K, Mitsui H, Sekiya R, Suzuki S, Shibata K, Callen D, Kikkawa F. PRIMA-1MET induces apoptosis through accumulation of intracellular reactive oxygen species irrespective of p53 status and chemo-sensitivity in epithelial ovarian cancer cells. Oncol Rep. 2016;35:2543-52.

Piantino c, Reis ST, Viana NI, Silva IA, Morais DR, Antunes AA, Dip N, Srougi M, Leite KR. PRIMA-1 induces apoptosis in bladder cancer cell lines by activating p53. Clinics (Sao Paulo). 2013;68(3):297-303.

Wang T, Lee K, Rehman A, Daoud SS. PRIMA-1 induces apoptosis by inhibiting JNK signaling but promoting the activation of Bax. Biochem Biophys Res Commun. 2007;352(1):203-12.

Lambert JM, Moshfegh A, Hainaut P, Wiman KG, Bykov VJ. Mutant p53 reactivation by PRIMA-1MET induces multiple signaling pathways converging on apoptosis. Oncogene. 2010;29(9):1329-38.

Saha MN, Abdi J, Yang Y, Chang H. miRNA-29a as a tumor suppressor mediates PRIMA-1Met-induced anti-myeloma activity by targeting c-Myc. Oncotarget. 2016;7(6):7149-60.

Othman N and Nagoor NH. The Role of microRNAs in the Regulation of Apoptosis in Lung Cancer and Its Application in Cancer Treatment. Biomed Res Int. 2014;2014(Special issue):1-19.

Duan W, Gao L, Wu X, Wang L, Nana-Sinkam SP, Otterson GA, Villalona-Calero MA. MicroRNA-34a is an important component of PRIMA-1-induced apoptotic network in human cancer cells. Int J Cancer. 2010;127(2):313-20.




How to Cite

İmir NG. MicroRNA-29a plays a prominent role in PRIMA-1Met-induced apoptosis in ovarian cancer cells. Arch Biol Sci [Internet]. 2020Jul.1 [cited 2022Aug.7];72(2):173-9. Available from: https://www.serbiosoc.org.rs/arch/index.php/abs/article/view/4851