AUTHOR=Chen Yi-Fong , Yang Yung-Ning , Chu Hung-Ru , Huang Tung-Yung , Wang Shwu-Huey , Chen Han-Yu , Li Zi-Lin , Yang Yu-Chen S. H. , Lin Hung-Yun , Hercbergs Aleck , Whang-Peng Jacqueline , Wang Kuan , Davis Paul J. 

TITLE=Role of Integrin αvβ3 in Doxycycline-Induced Anti-Proliferation in Breast Cancer Cells

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=10

YEAR=2022

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2022.829788

DOI=10.3389/fcell.2022.829788

ISSN=2296-634X

ABSTRACT=<p>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 <italic>via</italic> 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 (<italic>PD-L1</italic>) 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 (<italic>CCND1</italic>) and <italic>c-Myc</italic> which play crucial roles in proliferation. It also inhibits <italic>PD-L1</italic> 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-NH<sub>2</sub>). 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-NH<sub>2</sub>. In addition, the specific mechanism of action associated with pERK1/2 inhibition <italic>via</italic> integrin αvβ3 is unknown for doxycycline treatment. On the other hand, our findings indicated that inhibiting ERK1/2 activation leads to suppression of <italic>PD-L1</italic> expression by doxycycline treatment. Furthermore, doxycycline-induced gene expressions are disturbed by a specific integrin αvβ3 inhibitor (HSDVHK-NH<sub>2</sub>) 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 <italic>PD-L1</italic> gene expression in estrogen receptor (ER)-negative breast cancer MDA-MB-231 cells.</p>