Abstract
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.
Highlights
Doxycycline is an antibiotic for bacterial infections
Because doxycycline suppressed cell growth in both ERpositive and negative breast cancer cells, we investigated whether doxycycline could stimulate the expression of proapoptotic genes and inhibit proliferative genes
Since doxycycline inhibited extracellular signal-regulated kinase 1/2 (ERK1/2) activation, we further investigated the role of integrin αvβ3 on the inhibitory effect of programmed death-ligand 1 (PD-L1) expression induced by doxycycline in MDA-MB-231 cells (Figure 6)
Summary
Doxycycline is an antibiotic for bacterial infections. previous studies indicate that doxycycline can promote apoptotic procedures to suppress cell growth in different kinds of cancers (Sun et al, 2009). Doxycycline suppresses lipopolysaccharide (LPS)-activated phosphorylation of p38 mitogen-activated protein kinase (MAPK) and nuclear translocation of nuclear factor kappa B (NF-κB) (Santa-Cecília et al, 2016) It inhibits focal adhesion kinase (FAK) phosphorylation and its transcription (Sun et al, 2009; Wang et al, 2015). The previous study reveals that doxycycline down-regulates integrin αvβ downstream FAK signaling in leukemia cells (Wang et al, 2015) Those observations encourage us to investigate that the activity of doxycycline may be controlled by an integrin αvβ3-dependent signal transduction pathway. In contrast to the antibiotic activity of doxycycline, it inhibits the activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and regulates genes that regulate cell proliferation by interacting with cell surface integrin αvβ in ER-negative breast cancer cells. The doxycycline-induced signal transductions via integrin αvβ play pivotal modulators in several gene expressions and anti-proliferation in breast cancer cells
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