title: Gefitinib resistance in HCC mahlavu cells: upregulation of CD133 expression, activation of IGF-1R signaling pathway, and enhancement of IGF-1R nuclear translocation.
abstract: Hepatocellular carcinoma (HCC) is the major form of primary liver cancer which accounts for more than half million deaths annually worldwide. While the incidence of HCC is still on the rise, options of treatment are limited and the overall survival rate is poor. The acquisition of cancer drug resistance remains one of the key hurdles to successful treatment. Clearly, a thorough understanding of the underlying mechanisms is needed for new strategies to design novel treatments and/or to improve the current therapies. In the present study, we examined the expression of cancer stem cell (CSC) marker CD133, the activation of insulin-like growth factor 1 receptor (IGF-1R) signaling, and the nuclear translocation of IGF-1R in HCC Mahlavu cells under the treatment of gefitinib, a cancer drug that inhibits epidermal growth factor receptor (EGFR) pathway. Our results demonstrated that Mahlavu cells exhibited strong gefitinib resistance and the CD133 expression level was dramatically increased (from 3.88% to 32%) after drug treatment. In addition, the gefitinib treated cells displayed increased levels of phosphorylation in IGF-1R and Akt, indicating the intensified activation of this cancer-associated signaling pathway. Moreover, we revealed that IGF-1R underwent nuclear translocation in gefitinib treated cells using confocal microscopy. The IGF-1R nuclear translocation was enhanced under gefitinib treatment and appeared in a dose-dependent manner. Our findings suggest that increased IGF-1R nuclear translocation after gefitinib treatment may contribute to the drug resistance and IGF1-R activation, which might also associate with the upregulation of CD133 expression.
authors.affiliation: Division of Transplantation, Department of Surgery, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Adam S
authors.initials: AS
authors.lastname: Bodzin
authors.forename: Zhengyu
authors.initials: Z
authors.lastname: Wei
authors.forename: Reginald
authors.initials: R
authors.lastname: Hurtt
authors.forename: Tina
authors.initials: T
authors.lastname: Gu
authors.forename: Cataldo
authors.initials: C
authors.lastname: Doria
mesh_terms: D000071916:AC133 Antigen; D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D015703:Antigens, CD / Q000235:genetics* / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077156:Gefitinib; D006023:Glycoproteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D010455:Peptides / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D014408:Biomarkers, Tumor; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides; D011799:Quinazolines; D066246:ErbB Receptors; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; D000077156:Gefitinib