SERMs (selective estrogen receptor modulator), acting as estrogen receptor β agonists in hepatocellular carcinoma cells, inhibit the transforming growth factor-α-induced migration via specific inhibition of AKT signaling pathway

• Published in: PloS one Vol. 17; no. 1; p. e0262485
• Main Authors: Matsushima-Nishiwaki, Rie, Yamada, Noriko, Hattori, Yuria, Hosokawa, Yui, Tachi, Junko, Hori, Takamitsu, Kozawa, Osamu
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.01.2022; Public Library of Science (PLoS)
• Subjects: Agonists; AKT protein; Antibodies; Apoptosis; Biology and Life Sciences; Biomedical materials; Breast cancer; c-Jun protein; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell adhesion & migration; Cell migration; Cell Movement; Cell Proliferation; Endometrial cancer; Endometrium; Estrogen Receptor beta - agonists; Estrogen receptors; Estrogens; Estrogens - pharmacology; Gender aspects; Gene Expression Regulation, Neoplastic - drug effects; Growth factors; Hepatitis; Hepatocellular carcinoma; Hormone replacement therapy; Humans; Indoles - pharmacology; JNK protein; Kinases; Laboratories; Liver cancer; Liver Neoplasms - drug therapy; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; MAP kinase; Medicine; Medicine and Health Sciences; Men; Metastasis; Morbidity; Osteoporosis; Pharmacology; Phosphorylation; Post-menopause; Protein kinase; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Raloxifene; Raloxifene Hydrochloride - pharmacology; Receptors; Research and Analysis Methods; Selective estrogen receptor modulators; Selective Estrogen Receptor Modulators - pharmacology; Sex differences; Signal transduction; Signaling; Tamoxifen; Tamoxifen - pharmacology; Transcription factors; Transforming growth factor-a; Tumor Cells, Cultured; Tumors; University graduates; Uterus; Womens health; United Kingdom > UK; Japan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0262485

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.