title: Danusertib Induces Apoptosis, Cell Cycle Arrest, and Autophagy but Inhibits Epithelial to Mesenchymal Transition Involving PI3K/Akt/mTOR Signaling Pathway in Human Ovarian Cancer Cells.
abstract: Ovarian carcinoma (OC) is one of the most common gynecological malignancies, with a poor prognosis for patients at advanced stage. Danusertib (Danu) is a pan-inhibitor of the Aurora kinases with unclear anticancer effect and underlying mechanisms in OC treatment. This study aimed to examine the cancer cell killing effect and explore the possible mechanisms with a focus on proliferation, cell cycle progression, apoptosis, autophagy, and epithelial to mesenchymal transition (EMT) in human OC cell lines C13 and A2780cp. The results showed that Danu remarkably inhibited cell proliferation, induced apoptosis and autophagy, and suppressed EMT in both cell lines. Danu arrested cells in G₂/M phase and led to an accumulation of polyploidy through the regulation of the expression key cell cycle modulators. Danu induced mitochondria-dependent apoptosis and autophagy in dose and time-dependent manners. Danu suppressed PI3K/Akt/mTOR signaling pathway, evident from the marked reduction in the phosphorylation of PI3K/Akt/mTOR, contributing to the autophagy inducing effect of Danu in both cell lines. In addition, Danu inhibited EMT. In aggregate, Danu exerts potent inducing effect on cell cycle arrest, apoptosis, and autophagy, but exhibits a marked inhibitory effect on EMT. PI3K/Akt/mTOR signaling pathway contributes, partially, to the cancer cell killing effect of Danu in C13 and A2780cp cells.
authors.affiliation: Department of Obstetrics and Gynecology, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, China. danzi@health.usf.edu.|Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL 33612, USA. danzi@health.usf.edu.
authors.forename: Dan
authors.initials: D
authors.lastname: Zi
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL 33612, USA. zzhou1@health.usf.edu.
authors.forename: Zhi-Wei
authors.initials: ZW
authors.lastname: Zhou
authors.affiliation: Department of Obstetrics and Gynecology, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, China. yyjgmc@outlook.com.|Department of Gynecologic Oncology Surgery, Affiliated Cancer Hospital of Guizhou Medical University, Guiyang 550002, China. yyjgmc@outlook.com.
authors.forename: Ying-Jie
authors.initials: YJ
authors.lastname: Yang
authors.affiliation: Department of Obstetrics and Gynecology, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, China. hlgmc@outlook.com.
authors.forename: Lin
authors.initials: L
authors.lastname: Huang
authors.affiliation: Department of Obstetrics and Gynecology, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, China. zzlgmc@outlook.com.
authors.forename: Zun-Lun
authors.initials: ZL
authors.lastname: Zhou
authors.affiliation: Department of Obstetrics and Gynecology, Xiaolan Hospital, Southern Medical University, Zhongshan 528415, China. smhxlh@outlook.com.
authors.forename: Shu-Ming
authors.initials: SM
authors.lastname: He
authors.affiliation: Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Center &amp; Sino-US Joint Laboratory for Medical Sciences, Guizhou Medical University, Guiyang 550004, China. hzx@gmc.edu.cn.
authors.forename: Zhi-Xu
authors.initials: ZX
authors.lastname: He
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL 33612, USA. szhou@health.usf.edu.
authors.forename: Shu-Feng
authors.initials: SF
authors.lastname: Zhou
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005260:Female; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology*; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011720:Pyrazoles; D058570:TOR Serine-Threonine Kinases; C523797:danusertib
keywords: apoptosis; autophagy; cell cycle; danusertib; epithelial to mesenchymal transition; ovarian cancer