title: Apicidin-resistant HA22T hepatocellular carcinoma cells massively promote pro-survival capability via IGF-IR/PI3K/Akt signaling pathway activation.
abstract: Despite rapid advances in the diagnostic and surgical procedures, hepatocellular carcinoma (HCC) remains one of the most difficult human malignancies to treat. This may be due to the chemoresistant behaviors of HCC. It is believed that acquired resistance could be overcome and improve the overall survival of HCC patients by understanding the mechanisms of chemoresistance in HCC. A stable HA22T cancer line, which is chronically resistant to a histone deacetylase inhibitor, was established. After comparing the molecular mechanism of apicidin-R HA22T cells to parental ones by Western blotting, cell cycle-regulated proteins did not change in apicidin-R cells, but apicidin-R cells were more proliferative and had higher tumor growth (wound-healing assay and nude mice xenograft model). Moreover, apicidin-R cells displayed increased levels of p-IGF-IR, p-PI3K, p-Akt, Bcl-xL, and Bcl-2 but also significantly inhibited the tumor suppressor PTEN protein and apoptotic pathways when compared to the parental strain. Therefore, the highly proliferative effect of apicidin-R HA22T cells was blocked by Akt knockdown. For all these findings, we believe that novel strategies to attenuate IGF-IR/PI3K/Akt signaling could overcome chemoresistance toward the improvement of overall survival of HCC patients.
authors.affiliation: Division of Colorectal Surgery, Mackay Memorial Hospital, Taipei, Taiwan.
authors.forename: Hsi-Hsien
authors.initials: HH
authors.lastname: Hsu
authors.forename: Li-Hao
authors.initials: LH
authors.lastname: Cheng
authors.forename: Tsung-Jung
authors.initials: TJ
authors.lastname: Ho
authors.forename: Wei-Wen
authors.initials: WW
authors.lastname: Kuo
authors.forename: Yueh-Min
authors.initials: YM
authors.lastname: Lin
authors.forename: Ming-Cheng
authors.initials: MC
authors.lastname: Chen
authors.forename: Nien-Hung
authors.initials: NH
authors.lastname: Lee
authors.forename: Fuu-Jen
authors.initials: FJ
authors.lastname: Tsai
authors.forename: Kun-Hsi
authors.initials: KH
authors.lastname: Tsai
authors.forename: Chih-Yang
authors.initials: CY
authors.lastname: Huang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D055785:Gene Knockdown Techniques; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D010456:Peptides, Cyclic / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D056572:Histone Deacetylase Inhibitors; D010456:Peptides, Cyclic; C102351:apicidin; D019869:Phosphatidylinositol 3-Kinases; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt