Abstract
(3R,6R)-bassiatin(1) was isolated from the endogenous fungus, Fusarium oxysporum J8-1-2. Previous studies showed that (3R,6R)-bassiatin(1) has anti-oestrogen properties which make it cytotoxic to ER (oestrogen receptor)-positive breast cancer cells (MCF-7) by cell cycle arrest and induction of apoptosis. (3R,6R)-bassiatin(1) suppresses mRNA and protein expression of the ERα and oestrogen responsive genes of cyclin D1 and PR. We have investigated the interaction between (3R,6R)-bassiatin(1) and ERα and followed the roles of ERK (extracellular-signal-regulated kinase), Akt and GSK3β (glycogen synthase kinase 3β) during (3R,6R)-bassiatin(1)-induced apoptosis of MCF-7 cells. (3R,6R)-bassiatin(1) competed with E2 (17β-estradiol) for ERα active sites to inhibit ERα activation. However, while ERK1/2 and Akt were activated, GSK3β was inactivated during (3R,6R)-bassiatin(1)-induced apoptosis, suggesting that this compound is indeed an anti-oestrogen agent that can also activate the survival signalling pathway. Apoptosis caused by (3R,6R)-bassiatin(1) may be related to activation of ERK.
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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Apoptosis / drug effects*
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Breast Neoplasms
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Cell Cycle / drug effects
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Cell Line, Tumor
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Dose-Response Relationship, Drug
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Estradiol / metabolism
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Estrogen Antagonists / pharmacology*
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Estrogen Receptor alpha / antagonists & inhibitors
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Estrogen Receptor alpha / genetics
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Estrogen Receptor alpha / metabolism
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Extracellular Signal-Regulated MAP Kinases / genetics
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Female
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Fusarium / chemistry
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Gene Expression Regulation, Neoplastic / drug effects*
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Glycogen Synthase Kinase 3 / genetics
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Glycogen Synthase Kinase 3 / metabolism
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Glycogen Synthase Kinase 3 beta
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Humans
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Models, Molecular
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Morpholines / pharmacology*
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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Signal Transduction / drug effects*
Substances
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Antineoplastic Agents
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Estrogen Antagonists
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Estrogen Receptor alpha
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Morpholines
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Estradiol
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lateritin
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GSK3B protein, human
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Glycogen Synthase Kinase 3 beta
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Proto-Oncogene Proteins c-akt
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Extracellular Signal-Regulated MAP Kinases
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Glycogen Synthase Kinase 3