CD133⁺ melanoma subpopulation acquired resistance to caffeic acid phenethyl ester-induced apoptosis is attributed to the elevated expression of ABCB5: significance for melanoma treatment
Authors: Robert T Brodell
Heather A Drummond
Jesus Monico
Mohamed Hassan
Youssef Haikel
Natale T Sheehan
Abdelouahid El-Khattouti
Mosaad Megahed
Journal: Cancer Letters (2015)
Discipline: CLINICAL MEDICINE
Keywords: CAPE; CD133; CSC; E2F1; MAP kinase
Affiliations: Cancer Institute, University of Mississippi Medical Center, Jackson, MS 39 216, USA., Department of Pathology, University of Mississippi Medical Center, Jackson, MS 39 216, USA., Institut National de la Santé et de la Recherche Médicale, U1121, University of Strasbourg, Strasbourg 67000, France., 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., Department of Dermatology, University of Mississippi Medical Center, Jackson, MS 39 216, USA., Clinic of Dermatology, University Hospital of Aachen, Pauwelsstr. 30, Aachen 52074, Germany., 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: .

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. 

Retracted: No

PubPeer comments:
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