CD133+ melanoma subpopulation acquired resistance to caffeic acid phenethyl ester-induced apoptosis is attributed to the elevated expression of ABCB5: Significance for melanoma treatment. Issue 1 (1st February 2015)

• Record Type: Journal Article
• Authors: El-Khattouti, Abdelouahid; Sheehan, Natale T.; Monico, Jesus; Drummond, Heather A.; Haikel, Youssef; Brodell, Robert T.; Megahed, Mosaad; Hassan, Mohamed
• Is Part Of: Cancer letters. Volume 357:Issue 1(2015)
• Page Start: 83
• Page End: 104
• Publication Date: 2015-02-01
• Subjects: Melanoma -- CSC -- CAPE -- E2F1 -- CD133 -- MAP kinase; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2014.10.043
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: According to the cancer stem-like cell (CSC) hypothesis, neoplastic clones are maintained by a small fraction of cells with stem cell properties. Also, melanoma resistance to chemo- and radiotherapy is thought to be attributed to melanoma stem-like cells (MSCs). Caffeic acid phenethyl ester (CAPE) is a bioactive molecule, whose antitumor activity is approved in different tumor types. CAPE induced both apoptosis and E2F1 expression in CD133 −, but not in CD133 + melanoma subpopulations. The resistance of CD133 + melanoma subpopulation is attributed to the enhanced drug efflux mediated by ATP-binding cassette sub-family B member 5 (ABCB5), since the knockdown of ABCB5 was found to sensitize CD133 + cells to CAPE. CAPE-induced apoptosis is mediated by E2F1 as evidenced by the abrogation of apoptosis induced in response to the knockdown of E2F1. The functional analysis of E2F1 in CD133 + melanoma subpopulation demonstrated the ability of E2F1 gene transfer to trigger apoptosis of CD133 + cells and to enhance the activation of apoptosis signal-regulating kinase (ASK1), c-Jun N-terminal kinase and p38, and the DNA-binding activities of the transcription factors AP-1 and p53. Also, the induction of E2F1 expression was found to enhance the expression of the pro-apoptotic proteins Bax, Noxa and Puma, and to suppress the anti-apoptotic protein Mcl-1. Using specific pharmacological inhibitors we could demonstrate that E2F1 overcomes the chemo-resistance of MSCs/CD133 + cells by a mechanism mediated by both mitochondrial dysregulation and ER-stress-dependent pathways. In conclusion, our data addresses the mechanisms of CAPE/E2F1-induced apoptosis of chemo-resistant CD133 + melanoma subpopulation.