Ell3 stabilizes p53 following CDDP treatment via its effects on ubiquitin-dependent and -independent proteasomal degradation pathways in breast cancer cells

// Hee-Jin Ahn 1 , Kwang-Soo Kim 1 , Kyung-Won Shin 2 , Kee-Hwan Lim 1 , Jin-Ock Kim 1 , Je-Yong Lee 1 , Jiewan Kim 1 , Ji-Hoon Park 1 , Kyung-Min Yang 3 , Kwang-Hyun Baek 1 , Jeong-Jae Ko 1 , Kyung-Soon Park 1 1 Department of Biomedical Science, College of Life Science and CHA Stem Cell Institute, CHA University, Seoul, Korea 2 Graduate School of Biomedical Science, CHA University, Seoul, Korea 3 Department of Biomedical Science, College of Life Science and CHA Cancer Institute, CHA University, Seoul, Korea Correspondence to: Kyung-Soon Park, e-mail: kspark@cha.ac.kr Keywords: Ell3, p53, cis-diamminedichloroplatinum(II) (CDDP), NAD(P)H quinone oxidoreductase 1 (NQO1), interleukin-20 (IL20) Received: April 27, 2015 Accepted: October 09, 2015 Published: October 19, 2015 ABSTRACT The tumor suppressor protein p53 is unstable in quiescent cells and undergoes proteosomal degradation. Under conditions of cellular stress, p53 is rapidly stabilized by post-translational modification, thereby escaping degradation and translocating to the nucleus where it activates genes related to cell cycle arrest or apoptosis. Here, we report that the transcription elongation factor Ell3 sensitizes luminal type-cancer cell line, MCF7, which have wild-type p53, to the chemotherapeutic agent cis-diamminedichloroplatinum(II) (CDDP) by stabilizing p53. Overexpression of Ell3 in MCF7 cells suppressed the MDM2-mediated ubiquitin-dependent degradation pathway. In addition, Ell3 promoted binding of p53 to NADH quinone oxidoreductase 1, which is linked to the ubiquitin-independent degradation of p53. We found that Ell3 activates interleukin-20 (IL20) expression, which is linked to the ERK1/2 signaling pathway. Chemical inhibition of ERK1/2 signaling or molecular suppression of IL20 revealed that the ERK1/2 signaling pathway and IL20 are the main causes of p53 stabilization in Ell3-overexpressing MCF7 cells. These findings suggest that the ERK1/2 pathway can be targeted in the rational development of therapies to induce chemosensitization of breast cancer cells.