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
Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
Graduate Institute of Nanomedicine and Medical Engineering, College of Medical Engineering, Taipei Medical University, Taipei, Taiwan.
Front Cell Dev Biol. 2022 Feb 14;10:829788. doi: 10.3389/fcell.2022.829788. eCollection 2022.
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 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 () 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 () and which play crucial roles in proliferation. It also inhibits 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). 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. In addition, the specific mechanism of action associated with pERK1/2 inhibition integrin αvβ3 is unknown for doxycycline treatment. On the other hand, our findings indicated that inhibiting ERK1/2 activation leads to suppression of expression by doxycycline treatment. Furthermore, doxycycline-induced gene expressions are disturbed by a specific integrin αvβ3 inhibitor (HSDVHK-NH) 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 gene expression in estrogen receptor (ER)-negative breast cancer MDA-MB-231 cells.
强力霉素是一种抗生素，在不同类型的癌症中可抑制不同的信号转导途径，如抗炎和抗增殖。然而，强力霉素与整合素αvβ3的抗癌机制尚未完全明确。整合素αvβ3是一种细胞表面锚定蛋白。它是雌激素、雄激素和甲状腺激素的作用靶点，在癌细胞的增殖、迁移和血管生成过程中起关键作用。在我们之前的研究中，甲状腺激素可与整合素αvβ3相互作用以激活细胞外信号调节激酶1/2（ERK1/2），并上调程序性死亡配体1（）的表达。在本研究中，我们研究了强力霉素对两种乳腺癌细胞系MCF-7和MDA-MB-231细胞增殖的抑制作用。强力霉素在两种乳腺癌细胞系中均诱导浓度依赖性的抗增殖作用。它调节参与增殖、促凋亡和血管生成的基因表达。强力霉素抑制在增殖中起关键作用的细胞周期蛋白D1（）和。它还抑制基因表达。我们的研究结果表明，整合素αvβ3抑制剂（HSDVHK-NH）对整合素αvβ3结合活性的调节改变了甲状腺激素和强力霉素诱导的信号转导。强力霉素激活整合素下游的粘着斑激酶（FAK）的磷酸化，但抑制ERK1/2的磷酸化。无论如何，强力霉素诱导的FAK磷酸化被HSDVHK-NH阻断。此外，强力霉素治疗中与pERK1/2抑制和整合素αvβ3相关的具体作用机制尚不清楚。另一方面，我们的研究结果表明，抑制ERK1/2激活导致强力霉素治疗抑制的表达。此外，强力霉素诱导的基因表达受到特异性整合素αvβ3抑制剂（HSDVHK-NH）或丝裂原活化蛋白激酶（MAPK）/细胞外信号调节激酶（ERK）激酶（MAPK/ERK，MEK）抑制剂（PD98059）的干扰。结果表明，强力霉素可能与整合素αvβ3相互作用并抑制ERK1/2激活，从而调节雌激素受体（ER）阴性乳腺癌MDA-MB-231细胞的增殖并下调基因表达。
