TY - JOUR
T1 - Role of Integrin αvβ3 in Doxycycline-Induced Anti-Proliferation in Breast Cancer Cells
AU - Chen, Yi Fong
AU - Yang, Yung Ning
AU - Chu, Hung Ru
AU - Huang, Tung Yung
AU - Wang, Shwu Huey
AU - Chen, Han Yu
AU - Li, Zi Lin
AU - Yang, Yu Chen S.H.
AU - Lin, Hung Yun
AU - Hercbergs, Aleck
AU - Whang-Peng, Jacqueline
AU - Wang, Kuan
AU - Davis, Paul J.
N1 - Funding Information:
This work was supported in part by an intra-institutional grant from E-Da Medical Center (EDAHP108048, EDAHP109013 to Y-NY), by the Chair Professor Research Fund to KW and to JW-P, and the TMU Research Center of Cancer Translational Medicine from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project, by the Ministry of Education (MOE) in Taiwan (DP2-107-20000), and by grants from the Ministry of Science and Technology, Taiwan (MOST 109-2314-B-038-038 to Y-CSHY MOST 109-2124-M-038-001 to JW-P, MOST 110-2314-B-038-119 to KW, MOST 109-2314-B-038-125 to H-YL).
Publisher Copyright:
Copyright © 2022 Chen, Yang, Chu, Huang, Wang, Chen, Li, Yang, Lin, Hercbergs, Whang-Peng, Wang and Davis.
PY - 2022/2/14
Y1 - 2022/2/14
N2 - Doxycycline, an antibiotic, displays the inhibition of different signal transduction pathways, such as anti-inflammation and anti-proliferation, in different types of cancers. However, the anti-cancer mechanisms of doxycycline via integrin αvβ3 are incompletely understood. Integrin αvβ3 is a cell-surface anchor protein. It is the target for estrogen, androgen, and thyroid hormone and plays a pivotal role in the proliferation, migration, and angiogenic process in cancer cells. In our previous study, thyroxine hormones can interact with integrin αvβ3 to activate the extracellular signal-regulated kinase 1/2 (ERK1/2), and upregulate programmed death-ligand 1 (PD-L1) expression. In the current study, we investigated the inhibitory effects of doxycycline on proliferation in two breast cancer cell lines, MCF-7 and MDA-MB-231 cells. Doxycycline induces concentration-dependent anti-proliferation in both breast cancer cell lines. It regulates gene expressions involved in proliferation, pro-apoptosis, and angiogenesis. Doxycycline suppresses cell cyclin D1 (CCND1) and c-Myc which play crucial roles in proliferation. It also inhibits PD-L1 gene expression. Our findings show that modulation on integrin αvβ3 binding activities changed both thyroxine- and doxycycline-induced signal transductions by an integrin αvβ3 inhibitor (HSDVHK-NH2). Doxycycline activates phosphorylation of focal adhesion kinase (FAK), a downstream of integrin, but inhibits the ERK1/2 phosphorylation. Regardless, doxycycline-induced FAK phosphorylation is blocked by HSDVHK-NH2. In addition, the specific mechanism of action associated with pERK1/2 inhibition via integrin αvβ3 is unknown for doxycycline treatment. On the other hand, our findings indicated that inhibiting ERK1/2 activation leads to suppression of PD-L1 expression by doxycycline treatment. Furthermore, doxycycline-induced gene expressions are disturbed by a specific integrin αvβ3 inhibitor (HSDVHK-NH2) or a mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinases (ERK) kinase (MAPK/ERK, MEK) inhibitor (PD98059). The results imply that doxycycline may interact with integrin αvβ3 and inhibits ERK1/2 activation, thereby regulating cell proliferation and downregulating PD-L1 gene expression in estrogen receptor (ER)-negative breast cancer MDA-MB-231 cells.
AB - Doxycycline, an antibiotic, displays the inhibition of different signal transduction pathways, such as anti-inflammation and anti-proliferation, in different types of cancers. However, the anti-cancer mechanisms of doxycycline via integrin αvβ3 are incompletely understood. Integrin αvβ3 is a cell-surface anchor protein. It is the target for estrogen, androgen, and thyroid hormone and plays a pivotal role in the proliferation, migration, and angiogenic process in cancer cells. In our previous study, thyroxine hormones can interact with integrin αvβ3 to activate the extracellular signal-regulated kinase 1/2 (ERK1/2), and upregulate programmed death-ligand 1 (PD-L1) expression. In the current study, we investigated the inhibitory effects of doxycycline on proliferation in two breast cancer cell lines, MCF-7 and MDA-MB-231 cells. Doxycycline induces concentration-dependent anti-proliferation in both breast cancer cell lines. It regulates gene expressions involved in proliferation, pro-apoptosis, and angiogenesis. Doxycycline suppresses cell cyclin D1 (CCND1) and c-Myc which play crucial roles in proliferation. It also inhibits PD-L1 gene expression. Our findings show that modulation on integrin αvβ3 binding activities changed both thyroxine- and doxycycline-induced signal transductions by an integrin αvβ3 inhibitor (HSDVHK-NH2). Doxycycline activates phosphorylation of focal adhesion kinase (FAK), a downstream of integrin, but inhibits the ERK1/2 phosphorylation. Regardless, doxycycline-induced FAK phosphorylation is blocked by HSDVHK-NH2. In addition, the specific mechanism of action associated with pERK1/2 inhibition via integrin αvβ3 is unknown for doxycycline treatment. On the other hand, our findings indicated that inhibiting ERK1/2 activation leads to suppression of PD-L1 expression by doxycycline treatment. Furthermore, doxycycline-induced gene expressions are disturbed by a specific integrin αvβ3 inhibitor (HSDVHK-NH2) or a mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinases (ERK) kinase (MAPK/ERK, MEK) inhibitor (PD98059). The results imply that doxycycline may interact with integrin αvβ3 and inhibits ERK1/2 activation, thereby regulating cell proliferation and downregulating PD-L1 gene expression in estrogen receptor (ER)-negative breast cancer MDA-MB-231 cells.
KW - anti-proliferation
KW - breast cancer
KW - doxycycline
KW - integrin αvβ3
KW - signal transduction
UR - http://www.scopus.com/inward/record.url?scp=85125867877&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85125867877&partnerID=8YFLogxK
U2 - 10.3389/fcell.2022.829788
DO - 10.3389/fcell.2022.829788
M3 - Article
AN - SCOPUS:85125867877
SN - 2296-634X
VL - 10
JO - Frontiers in Cell and Developmental Biology
JF - Frontiers in Cell and Developmental Biology
M1 - 829788
ER -
