The cell cycle effects of docosahexaenoic acid on human metastatic hepatocellular carcinoma proliferation

Int J Oncol. 2010 Apr;36(4):991-8. doi: 10.3892/ijo_00000579.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology*
  • Carcinoma, Hepatocellular / secondary
  • Cell Adhesion / drug effects
  • Cell Cycle / drug effects*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Cyclin A / metabolism
  • Cyclin E / metabolism
  • Cyclin-Dependent Kinase 2 / metabolism
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 / metabolism
  • DNA Replication / drug effects
  • Docosahexaenoic Acids / pharmacology*
  • Dose-Response Relationship, Drug
  • Gene Expression Regulation, Enzymologic / drug effects
  • Gene Expression Regulation, Neoplastic / drug effects
  • HSP27 Heat-Shock Proteins / metabolism
  • Heat-Shock Proteins / metabolism
  • Humans
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology*
  • Molecular Chaperones
  • Proto-Oncogene Proteins c-myc / metabolism
  • RNA, Messenger / metabolism
  • Superoxide Dismutase / metabolism
  • Time Factors

Substances

  • Antineoplastic Agents
  • Cyclin A
  • Cyclin E
  • HSP27 Heat-Shock Proteins
  • HSPB1 protein, human
  • Heat-Shock Proteins
  • Molecular Chaperones
  • Proto-Oncogene Proteins c-myc
  • RNA, Messenger
  • Docosahexaenoic Acids
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Superoxide Dismutase
  • CDK2 protein, human
  • Cyclin-Dependent Kinase 2
  • molecular chaperone GRP78