Holothuria tubulosa Extract Represses Proliferation and HIF-α Activity by Inhibiting Erk1/2 Phosphorylation in Liver Cancer Cell Line under Hypoxia

Abstract

Holothurians are prominent marine organisms in benthic ecosystems, exploited as food for centuries and, recently, as nutraceuticals. Moreover, they constitute a significant source of beneficial and medicinally valuable metabolites that have anticancer properties. Hypoxia, or low oxygen levels, and the stimulation of HIFs as a result of rapid cell proliferation and a restricted blood supply are characteristics shared by the majority of cancers, which give them resistance to standard treatment. The present study examines the effect of Holothuria tubulosa extract on the proliferation, HIF-α protein expression, and their transcriptional activity in hepatocarcinoma-derived Huh7 cells. Specimens of H. tubulosa were collected from the Aegean Sea, and their extract decreased the proliferation in Huh7 cells under normoxia and hypoxia in a dose-dependent manner by MTT assay. The extract modified HIF-1α protein expression by western blot analysis, downregulated hypoxia-induced VEGF promoter by luciferase assay, and decreased the expression of known HIF-1 and HIF-2-specific target genes, PGK and EPO, as revealed by real-time PCR. H. tubulosa extract had the ability to reduce the phosphorylated form of ERK1/2 explaining its inhibitory effect on proliferation and HIF activity. These data reveal new roles of H. tubulosa with promising anticancer properties in liver cancer cells.