Lee Woo-Jin, Jung Eun-Ju, Hwang Ju-Mi, Bae Jeong-Won, Kwon Woo-Sung
Department of Animal Science and Biotechnology, Kyungpook National University, Sangju, Gyeongsangbuk-do 37224, South Korea.
Department of Animal Science and Biotechnology, Kyungpook National University, Sangju, Gyeongsangbuk-do 37224, South Korea.
Reprod Toxicol. 2022 Oct;113:103-109. doi: 10.1016/j.reprotox.2022.08.008. Epub 2022 Aug 13.
Glucose-regulated protein 78 (GRP78), which is commonly found in the endoplasmic reticulum (ER), is involved in stabilizing ER proteins and inducing the unfolded protein response. Furthermore, GRP78 is expressed on the surface of most common cancer cells, such as cells of breast, lung, liver, and prostate cancers, and plays a role in apoptosis and cell proliferation via the PI3K/PDK1/AKT signaling pathway. Therefore, various trials have been performed for evaluating cancer treatment by inhibiting GRP78. Moreover, GRP78 is expressed on the surface of spermatozoa; however, its role in spermatozoa physiology remains unclear. Therefore, this study was designed to investigate the effects of GRP78 on sperm function during capacitation and elucidate the underlying mechanisms. Boar spermatozoa were exposed to various concentrations of HA15, a GRP78 antagonist, and sperm kinematic parameters, capacitation status, cell viability, levels of PI3K/PDK1/AKT-pathway related proteins, and tyrosine phosphorylation were evaluated. GRP78 inhibition significantly decreased sperm motility, kinematic parameters, capacitated and acrosome-reacted spermatozoa counts, and cell viability. Moreover, GRP78 expression was significantly decreased in HA15-treated spermatozoa compared to that in the control group, and levels of PI3K/PDK1/AKT-pathway related proteins changed significantly. Furthermore, tyrosine phosphorylation was significantly altered in the HA15-treated group. The results of this study suggest that GRP78 inhibition in cancer therapy may negatively affect sperm function. These results lay a strong foundation for future studies aiming to identify the molecular mechanisms related to GRP78 in spermatozoa.
葡萄糖调节蛋白78（GRP78）通常存在于内质网（ER）中，参与稳定内质网蛋白并诱导未折叠蛋白反应。此外，GRP78在大多数常见癌细胞表面表达，如乳腺癌、肺癌、肝癌和前列腺癌细胞，通过PI3K/PDK1/AKT信号通路在细胞凋亡和增殖中发挥作用。因此，已经进行了各种试验来评估通过抑制GRP78进行癌症治疗的效果。此外，GRP78在精子表面表达；然而，其在精子生理中的作用仍不清楚。因此，本研究旨在探讨GRP78在精子获能过程中对精子功能的影响，并阐明其潜在机制。将公猪精子暴露于不同浓度的GRP78拮抗剂HA15中，评估精子运动参数、获能状态、细胞活力、PI3K/PDK1/AKT信号通路相关蛋白水平以及酪氨酸磷酸化情况。抑制GRP78可显著降低精子活力、运动参数、获能和顶体反应精子数量以及细胞活力。此外，与对照组相比，HA15处理的精子中GRP78表达显著降低，PI3K/PDK1/AKT信号通路相关蛋白水平也发生了显著变化。此外，HA15处理组的酪氨酸磷酸化也发生了显著改变。本研究结果表明，癌症治疗中抑制GRP78可能会对精子功能产生负面影响。这些结果为未来旨在确定精子中与GRP78相关分子机制的研究奠定了坚实基础。
