Abstract
Given the reported side effects associated with chemotherapy and surgical resection, dietary intervention with omega-3 polyunsaturated fatty acids (PUFAs) has been postulated to be an alterative way to prevent liver cancer progression and metastasis. We studied the effects of an omega-3 PUFA, docahexaenoic acid (DHA) on COX-2 expression and the cell cycle control machinery that co-ordinately regulate the HCC cells growth. Our data showed that DHA (0-200 microM) retarded proliferation of the human metastatic HCC cell line MHCC97L dose-dependently. In addition, inhibition of cyclin A/Cdk2 interfered with S-phase progression further in agreement with the result of bivariate flow cytometric analysis which indicated that DNA synthesis time (Ts) was significantly prolonged by DHA in MHCC97L. The N-myc oncogene, the heat shock proteins Hsp27 and glucose-related protein 78 (GRP78) as well as the antioxidant enzymes superoxide dismutase may play significant roles in the cell cycle control and reduced-proliferation of MHCC97L by DHA. Our data indicated that it is imperative to develop therapeutic strategy with omega-3 PUFA that simultaneously targets COX-2 and other cell cycle regulators in hepatocarcinogenesis. This study provides novel mechanistic insights into the modulation of DHA on human hepatocarcinoma.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / pharmacology*
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Carcinoma, Hepatocellular / genetics
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Carcinoma, Hepatocellular / metabolism
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Carcinoma, Hepatocellular / pathology*
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Carcinoma, Hepatocellular / secondary
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Cell Adhesion / drug effects
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Cell Cycle / drug effects*
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Cell Line, Tumor
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Cell Proliferation / drug effects*
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Cyclin A / metabolism
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Cyclin E / metabolism
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Cyclin-Dependent Kinase 2 / metabolism
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Cyclooxygenase 2 / genetics
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Cyclooxygenase 2 / metabolism
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DNA Replication / drug effects
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Docosahexaenoic Acids / pharmacology*
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Dose-Response Relationship, Drug
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Endoplasmic Reticulum Chaperone BiP
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Gene Expression Regulation, Enzymologic / drug effects
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Gene Expression Regulation, Neoplastic / drug effects
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HSP27 Heat-Shock Proteins / metabolism
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Heat-Shock Proteins / metabolism
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Humans
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Liver Neoplasms / genetics
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Liver Neoplasms / metabolism
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Liver Neoplasms / pathology*
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Molecular Chaperones
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Proto-Oncogene Proteins c-myc / metabolism
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RNA, Messenger / metabolism
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Superoxide Dismutase / metabolism
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Time Factors
Substances
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Antineoplastic Agents
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Cyclin A
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Cyclin E
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Endoplasmic Reticulum Chaperone BiP
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HSP27 Heat-Shock Proteins
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HSPA5 protein, human
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HSPB1 protein, human
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Heat-Shock Proteins
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Molecular Chaperones
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Proto-Oncogene Proteins c-myc
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RNA, Messenger
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Docosahexaenoic Acids
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Cyclooxygenase 2
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PTGS2 protein, human
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Superoxide Dismutase
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CDK2 protein, human
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Cyclin-Dependent Kinase 2