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.