title: 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.affiliation: Cancer Institute, University of Mississippi Medical Center, Jackson, MS 39 216, USA.
authors.forename: Abdelouahid
authors.initials: A
authors.lastname: El-Khattouti
authors.affiliation: Cancer Institute, University of Mississippi Medical Center, Jackson, MS 39 216, USA.
authors.forename: Natale T
authors.initials: NT
authors.lastname: Sheehan
authors.affiliation: Department of Pathology, University of Mississippi Medical Center, Jackson, MS 39 216, USA.
authors.forename: Jesus
authors.initials: J
authors.lastname: Monico
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U1121, University of Strasbourg, Strasbourg 67000, France.
authors.forename: Heather A
authors.initials: HA
authors.lastname: Drummond
authors.affiliation: Department of Operative Dentistry and Endodontics, Dental Faculty, University of Strasbourg, Strasbourg 67000, France; Department of Physiology and Biophysics, University of Mssisippi Medical Center Jackson, MS 39 216, USA.
authors.forename: Youssef
authors.initials: Y
authors.lastname: Haikel
authors.affiliation: Department of Dermatology, University of Mississippi Medical Center, Jackson, MS 39 216, USA.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Brodell
authors.affiliation: Clinic of Dermatology, University Hospital of Aachen, Pauwelsstr. 30, Aachen 52074, Germany.
authors.forename: Mosaad
authors.initials: M
authors.lastname: Megahed
authors.affiliation: Cancer Institute, University of Mississippi Medical Center, Jackson, MS 39 216, USA; Department of Operative Dentistry and Endodontics, Dental Faculty, University of Strasbourg, Strasbourg 67000, France; Department of Physiology and Biophysics, University of Mssisippi Medical Center Jackson, MS 39 216, USA. Electronic address: dr.hassan@gmx.de.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Hassan
mesh_terms: D000071916:AC133 Antigen; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis*; D015703:Antigens, CD / Q000096:biosynthesis*; D017209:Apoptosis / Q000502:physiology; D002109:Caffeic Acids / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D006023:Glycoproteins / Q000096:biosynthesis*; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010455:Peptides; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D015398:Signal Transduction
chemical_list: C480744:ABCB5 protein, human; D000071916:AC133 Antigen; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D015703:Antigens, CD; D002109:Caffeic Acids; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides; C055494:caffeic acid phenethyl ester; D010626:Phenylethyl Alcohol
keywords: CAPE; CD133; CSC; E2F1; MAP kinase; Melanoma