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Abstract
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)-α 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-α-induced HuH7 cell migration. ERB041 and DPN, estrogen receptor (ER) β agonists, inhibited the TGF-α-induced cell migration whereas PPT, an ERα agonist, did not show the suppressive effect on the cell migration. ERB041 attenuated the TGF-α-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-α. Furthermore, PHTPP, an ERβ antagonist, significantly reversed the suppression by both raloxifene and bazedoxifene of the TGF-α-induced cell migration. Taken together, our results strongly indicate that raloxifene and bazedoxifene, SERMs, suppress the TGF-α-induced migration of HCC cells through ERβ-mediated inhibition of the AKT signaling pathway.
Highlights
Selective estrogen receptor modulator (SERM) belongs to a class of compounds with non-steroidal structures that interact with estrogen receptors (ERs), ERα and ERβ [1,2,3,4]
It is generally known that two types of ER are recognized and denoted ERα and ERβ [1,2,3], and that ERα and ERβ exist in hepatocellular carcinoma (HCC) cells [15,16,17]
In order to investigate whether ERβ activated by raloxifene or bazedoxifene plays a suppressive role in the transforming growth factor (TGF)-α-induced migration of HuH7 cells, we examined the effect of PHTPP, an antagonist of ERβ [29], on the cell migration
Summary
Selective estrogen receptor modulator (SERM) belongs to a class of compounds with non-steroidal structures that interact with estrogen receptors (ERs), ERα and ERβ [1,2,3,4]. Estrogen has agonistic effects on various tissues especially breast and uterus, and the long term usage of estrogen increases the risk of breast and uterine cancer [1]. A SERM of the first-generation, which was developed as an ER antagonist for breast cancer treatment, plays as an agonist of ER in bone tissue and upregulates bone mass [1,2,3,4]. Bazedoxifene, a third-generation SERM, displays an agonistic effect on ER in bone and an antagonistic effect on ER in breast and endometrium [2]. In endometrium, bazedoxifene shows more strong antagonistic effect compared with raloxifene [2, 4]. Raloxifene and bazedoxifene are widely used as safer medicines for patients with osteoporosis as postmenopausal hormone replacement therapy [1,2,3,4]
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