Identification and analysis of CD133(+) melanoma stem-like cells conferring resistance to taxol: An insight into the mechanisms of their resistance and response.
The presence and the involvement of cancer stem-like cells (CSCs) in tumor initiation and progression, and chemo-resistance are documented. Herein, we functionally analyzed melanoma stem-like cells (MSC)/CD133(+) cells on their resistance and response to taxol-induced apoptosis. Besides being taxol resistant, the CD133(+) cells demonstrated a growth advantage over the CD133(-) subpopulation. Taxol induced apoptosis on CD133(-) cells, but not on CD133(+) cells. In the CD133(-) subpopulation, the exposure to taxol induced the activation of apoptosis signal-regulating kinase1 (ASK1)/c-jun-N-terminal kinase (JNK), p38, extracellular signal regulated kinase (ERK) pathways and Bax expression, while in CD133(+) cells taxol was able only to enhance the activity of the ERK pathway. In CD133(+) cells, the direct gene transfer of Bax overcame the acquired resistance to taxol. Taken together, our data provide an insight into the mechanistic cascade of melanoma resistance to taxol and suggest Bax gene transfer as a complementary approach to chemotherapy.
Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA.
Abdelouahid
A
El-Khattouti
Institut National de la Santé et de la Recherche Médicale, U 977, University of Strasbourg, 67000 Strasbourg, France; Department of Operative Dentistry and Endodontics, Dental Faculty, University of Strasbourg, 67000 Strasbourg, France.
Denis
D
Selimovic
Institut National de la Santé et de la Recherche Médicale, U 977, University of Strasbourg, 67000 Strasbourg, France; Department of Operative Dentistry and Endodontics, Dental Faculty, University of Strasbourg, 67000 Strasbourg, France.
Youssef
Y
Haïkel
Clinic of Dermatology, University Hospital of Aachen, Pauwelsstr. 30, 52074 Aachen, Germany.
Mosaad
M
Megahed
Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA.
Christian R
CR
Gomez
Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA; Institut National de la Santé et de la Recherche Médicale, U 977, University of Strasbourg, 67000 Strasbourg, France; Department of Operative Dentistry and Endodontics, Dental Faculty, University of Strasbourg, 67000 Strasbourg, France. Electronic address: dr.hassan@gmx.de.
Mohamed
M
Hassan
D000071916:AC133 Antigen; D015703:Antigens, CD / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005434:Flow Cytometry; D018014:Gene Transfer Techniques; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000166:cytology*; D017239:Paclitaxel / Q000494:pharmacology*; D010455:Peptides / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000071916:AC133 Antigen; D015703:Antigens, CD; C494826:BAX protein, human; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides; D051028:bcl-2-Associated X Protein; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D017239:Paclitaxel
Apoptosis; CD133; Cancer stem cells; JNK; P38; Taxol