title: Mitogen-activated protein kinase pathway is pivotal for anoikis resistance in metastatic hepatoma cells.
abstract: It is important for metastatic cancer cells to acquire anoikis resistance for survival in the circulatory system. In the present study, metastatic hepatoma cells were demonstrated to acquire anoikis resistance, which renders them more invasive, more resistant to anticancer agents and able to evade the host immune system for long‑term survival. One of the most significant characteristics of these anoikis‑resistant metastatic hepatoma cells is their proliferation inhibition. However, when microarray results were analyzed to identify the underlying molecular mechanism, the mitogen‑activated protein kinase (MAPK) signaling pathway was found to be markedly upregulated, which appeared to conflict with the proliferation inhibition state. To investigate this result and the associated mechanism, protein kinase inhibitors were used to inhibit the phosphatidylinositol 3‑kinase (PI-3K)/AKT and MAPK pathways. It was found that anoikis-resistant hepatoma cells may compensate for the inhibition of PI-3K/AKT or MAPK pathways by cross-talk between these two pathways, which increases their survival capacity during metastasis. In concordance with this result, western blot analysis revealed that the phosphorylation level of extracellular signal‑related kinase protein was increased when the PI-3K/AKT pathway was inhibited. Therefore, it was concluded that when metastatic hepatoma cells aggregate in blood vessels, proliferation is inhibited and the MAPK signaling pathway is upregulated, which increases the long‑term survival of the cells. Furthermore, a compensatory interplay between the AKT and MAPK signaling pathways was observed in the present study. Using kinase inhibitors for the two pathways in combination may yield a substantial advance in successfully producing a downstream phenotypic response in anoikis‑resistant metastatic hepatoma cells.
authors.affiliation: Medical Research Center, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, P.R. China.
authors.forename: Lili
authors.initials: L
authors.lastname: Cao
authors.affiliation: Department of Immunology, School of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Immunology, School of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China.
authors.forename: Lihui
authors.initials: L
authors.lastname: Han
authors.affiliation: Medical Research Center, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, P.R. China.
authors.forename: Juan
authors.initials: J
authors.lastname: Du
authors.affiliation: Department of Immunology, School of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Liang
authors.affiliation: Department of Pathophysiology, School of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China.
authors.forename: Yugang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Immunology, School of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China.
authors.forename: Wensheng
authors.initials: W
authors.lastname: Sun
mesh_terms: D023102:Anoikis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects; D002449:Cell Aggregation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009362:Neoplasm Metastasis; D020411:Oligonucleotide Array Sequence Analysis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases