Doxorubicin Induces ER Calcium Release via Src in Rat Ovarian Follicles

• Published in: Toxicological sciences Vol. 168; no. 1; pp. 171 - 178
• Main Authors: Aziz, Aziz Ur Rehman, Geng, Chunyang, Li, Wang, Yu, Xiaohui, Qin, Kai-Rong, Wang, Hanqin, Liu, Bo
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.03.2019
• Subjects: Animals; Apoptosis - drug effects; Calcium - metabolism; Cytosol - drug effects; Cytosol - metabolism; Doxorubicin - pharmacology; Endoplasmic Reticulum - drug effects; Endoplasmic Reticulum - metabolism; Female; Ovarian Follicle - drug effects; Ovarian Follicle - metabolism; Primary Cell Culture; Rats; Rats, Sprague-Dawley; Signal Transduction; src-Family Kinases - metabolism; ovarian follicles; FRET; doxorubicin; ovarian toxicity; calcium signaling
• ISSN: 1096-6080; 1096-0929
• DOI: 10.1093/toxsci/kfy284

Abstract Although doxorubicin has been widely used as an anticancer drug, it has dose-dependent toxic effects on ovarian follicle development and apoptosis, oocyte maturation, and hormone secretion. Ca2+ signaling also has vital roles in the same cellular functions of ovarian follicles, indicating a strong link with doxorubicin-induced ovarian toxicity. In the current project, doxorubicin-induced Ca2+ alternations in cultured rat ovarian follicles have been explored with the fluorescence resonance energy transfer technology. The results reveal that doxorubicin enhances the cytosolic Ca2+ level smoothly. Further experiments confirm that the endoplasmic reticulum (ER) calcium, but not the extracellular calcium influx, is the main source of intracellular calcium increase. Moreover, Src kinase activation could be the upstream of doxorubicin-induced ER calcium release. Therefore, this project demonstrates that doxorubicin increases the cytosolic Ca2+ mainly by releasing calcium from ER via Src kinase activation in ovarian follicles, which provides deeper understanding of doxorubicin-induced ovarian toxicity.