SERMs

Selective estrogen receptor modulator (SERM) interacts with estrogen receptors and acts as both an agonist or an antagonist, depending on the target tissue. SERM is widely used as a safer hormone replacement therapeutic medicine for postmenopausal osteoporosis. Regarding hepatocellular carcinoma (HC...

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Bibliographic Details
Published in:PloS one 2022-01, Vol.17 (1), p.e0262485
Main Authors: Matsushima-Nishiwaki, Rie, Yamada, Noriko, Hattori, Yuria, Hosokawa, Yui, Tachi, Junko, Hori, Takamitsu, Kozawa, Osamu
Format: Article
Language:English
Subjects:
Antagonists
Development and progression
Drug therapy
Estrogen
Health aspects
Hepatoma
Physiological aspects
Protein kinases
Transforming growth factors
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Summary:Selective estrogen receptor modulator (SERM) interacts with estrogen receptors and acts as both an agonist or an antagonist, depending on the target tissue. SERM is widely used as a safer hormone replacement therapeutic medicine for postmenopausal osteoporosis. Regarding hepatocellular carcinoma (HCC), accumulating evidence indicates gender differences in the development, and that men are at higher morbidity risk than premenopausal women, suggesting that estrogen protects against HCC. However, it remains unclear whether SERM affects the HCC progression. Previously, we have shown that transforming growth factor (TGF)-[alpha] promotes the migration of HCC cells via p38 mitogen-activated protein kinases (MAPK), c-Jun N-terminal kinase and AKT. In the present study, we investigated whether SERM such as tamoxifen, raloxifene and bazedoxifene, affects the HCC cell migration using human HCC-derived HuH7 cells. Raloxifene and bazedoxifene but not tamoxifen, significantly suppressed the TGF-[alpha]-induced HuH7 cell migration. ERB041 and DPN, estrogen receptor (ER) [beta] agonists, inhibited the TGF-[alpha]-induced cell migration whereas PPT, an ER[alpha] agonist, did not show the suppressive effect on the cell migration. ERB041 attenuated the TGF-[alpha]-induced phosphorylation of AKT without affecting the phosphorylation of p38 MAPK and c-Jun N-terminal kinase. Raloxifene and bazedoxifene also inhibited the phosphorylation of AKT by TGF-[alpha]. Furthermore, PHTPP, an ER[beta] antagonist, significantly reversed the suppression by both raloxifene and bazedoxifene of the TGF-[alpha]-induced cell migration. Taken together, our results strongly indicate that raloxifene and bazedoxifene, SERMs, suppress the TGF-[alpha]-induced migration of HCC cells through ER[beta]-mediated inhibition of the AKT signaling pathway.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0262485