CD133⁺ melanoma subpopulation acquired resistance to caffeic acid phenethyl ester-induced apoptosis is attributed to the elevated expression of ABCB5: significance for melanoma treatment.

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.

• Authors: Abdelouahid El-Khattouti, Natale T Sheehan, Jesus Monico, Heather A Drummond, Youssef Haikel, Robert T Brodell, Mosaad Megahed, Mohamed Hassan
• Journal: Cancer letters (Cancer Lett) Vol. 357 Issue 1 Pg. 83-104 (Feb 01 2015) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 25449786 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Published by Elsevier Ireland Ltd.

Chemical References

• ABCB5 protein, human
• AC133 Antigen
• ATP Binding Cassette Transporter, Subfamily B
• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antigens, CD
• Caffeic Acids
• Glycoproteins
• PROM1 protein, human
• Peptides
• caffeic acid phenethyl ester
• Phenylethyl Alcohol

Topics

• AC133 Antigen
• ATP Binding Cassette Transporter, Subfamily B
• ATP Binding Cassette Transporter, Subfamily B, Member 1 (biosynthesis)
• Antigens, CD (biosynthesis)
• Apoptosis (physiology)
• Caffeic Acids (pharmacokinetics, pharmacology)
• Cell Line, Tumor
• Drug Resistance, Neoplasm
• Glycoproteins (biosynthesis)
• Humans
• Melanoma (drug therapy, metabolism, pathology)
• Peptides
• Phenylethyl Alcohol (analogs & derivatives, pharmacokinetics, pharmacology)
• Signal Transduction