Oleuropein, a secoiridoid derived from olive tree, inhibits the proliferation of human colorectal cancer cell through downregulation of HIF-1α.
Oleuropein (OL) is the most prominent phenolic compound in the fruit of olive tree. Although OL has shown powerful anticancer activity the underlying action mechanism remains largely unknown. The present study evaluated the effects of OL on hydroxityrosol (HT)-29 human colon adenocarcinoma cells in comparison to hydroxytyrosol, its hydrolysis product, and to elucidate the underlying anticancer molecular mechanisms involved. Cell proliferation was determined using SRB assay. Cell cycle and apoptosis were assessed by flow cytometry and changes in MAPK cascade protein expression, HIF-1α, p53, PPARγ, and NFKβ signaling pathways by Western blot. Although OL showed less potency than HT, in terms of cell growth inhibition, induced significant changes in cell cycle analysis and caused a significant increase in the apoptotic population. Both compounds produced a remarkable decrease in HIF-1α protein and an upregulation of p53 protein expression. However, no significant changes in IkB-α and MAPK cascade protein expressions were observed. HT produced a significant upregulation in peroxisome proliferator-activated receptor gamma (PPARγ) expression whereas OL failed. PPARγ upregulation may be one of the principal mechanisms of the tumor shrinkage by HT. Our novel findings demonstrate that OL limits the growth and induces apoptosis in HT-29 cells via p53 pathway activation adapting the HIF-1α response to hypoxia.
Department of Pharmacology, Faculty of Pharmacy, University of Seville, Seville, Spain.
Ana
A
Cárdeno
Marina
M
Sánchez-Hidalgo
M Angeles
MA
Rosillo
Catalina
C
Alarcón de la Lastra
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation / Q000187:drug effects; D019073:HT29 Cells / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D020672:I-kappa B Proteins / Q000378:metabolism; D057888:Iridoid Glucosides; D039823:Iridoids; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D031658:Olea / Q000737:chemistry*; D047495:PPAR gamma / Q000378:metabolism; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives / Q000494:pharmacology; D011714:Pyrans / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D020672:I-kappa B Proteins; D057888:Iridoid Glucosides; D039823:Iridoids; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D047495:PPAR gamma; D011714:Pyrans; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C005975:3,4-dihydroxyphenylethanol; D000072000:NF-KappaB Inhibitor alpha; C002769:oleuropein; D048051:p38 Mitogen-Activated Protein Kinases; D010626:Phenylethyl Alcohol