Kwon Woo-Sung, Kim Ye-Ji, Ryu Do-Yeal, Kwon Ki-Jin, Song Won-Hee, Rahman Md Saidur, Pang Myung-Geol
Department of Animal Biotechnology, Kyungpook National University, Sangju, Gyeongsangbuk-do, 37224, Republic of Korea.
Department of Animal Science & Technology, Chung-Ang University, Anseong, Gyeonggi-Do, 17546, Republic of Korea.
Theriogenology. 2019 Mar 1;126:145-152. doi: 10.1016/j.theriogenology.2018.12.019. Epub 2018 Dec 8.
Fms-like tyrosine kinase 3 (FLT3) is a type III kinase that is highly expressed in seminal plasma of infertile men. FLT3 activation can be blocked by inhibition of its phosphorylation using the nontoxic and selective inhibitor, quizartinib. We investigated the function of FLT3 and the corresponding effects of quizartinib in mouse spermatozoa. Spermatozoa were treated with different concentrations (0.1, 1, 10, 20, and 30 μM) of quizartinib for 90 min at 37 °C in 5% CO in air. FLT3 was detected in capacitated and non-capacitated spermatozoa. While the level of FLT3 was unaffected, the levels of phospho-FLT3 were significantly altered in spermatozoa by quizartinib. Exposure of spermatozoa to higher concentrations of quizartinib significantly altered sperm viability, motility, motion kinematics, levels of intracellular ATP, and capacitation status. Fertilization and early embryonic development were suppressed by quizartinib. This may have occurred as a consequence of decreased protein kinase A (PKA) activity and tyrosine phosphorylation. The inhibition of FLT3 by quizartinib may affect the fertilization and embryonic development by reducing tyrosine phosphorylation through a PKA-dependent pathway. Our data implicate FLT3 as a biomarker for diagnosis and prognosis of male fertility. In addition, quizartinib has potential for development as a new contraceptive agent.
Fms样酪氨酸激酶3（FLT3）是一种III型激酶，在不育男性的精浆中高度表达。使用无毒且具有选择性的抑制剂奎扎替尼抑制其磷酸化，可阻断FLT3的激活。我们研究了FLT3的功能以及奎扎替尼对小鼠精子的相应影响。将精子在含5%二氧化碳的空气中于37°C用不同浓度（0.1、1、10、20和30 μM）的奎扎替尼处理90分钟。在获能和未获能的精子中均检测到FLT3。虽然FLT3的水平未受影响，但奎扎替尼使精子中磷酸化FLT3的水平发生了显著改变。使精子暴露于较高浓度的奎扎替尼会显著改变精子活力、运动能力、运动学参数、细胞内ATP水平和获能状态。奎扎替尼抑制受精和早期胚胎发育。这可能是蛋白激酶A（PKA）活性降低和酪氨酸磷酸化减少的结果。奎扎替尼对FLT3的抑制可能通过PKA依赖的途径减少酪氨酸磷酸化，从而影响受精和胚胎发育。我们的数据表明FLT3可作为男性生育力诊断和预后的生物标志物。此外，奎扎替尼有开发成为新型避孕药物的潜力。
