title: Alisertib Induces Cell Cycle Arrest, Apoptosis, Autophagy and Suppresses EMT in HT29 and Caco-2 Cells.
abstract: Colorectal cancer (CRC) is one of the most common malignancies worldwide with substantial mortality and morbidity. Alisertib (ALS) is a selective Aurora kinase A (AURKA) inhibitor with unclear effect and molecular interactome on CRC. This study aimed to evaluate the molecular interactome and anticancer effect of ALS and explore the underlying mechanisms in HT29 and Caco-2 cells. ALS markedly arrested cells in G₂/M phase in both cell lines, accompanied by remarkable alterations in the expression level of key cell cycle regulators. ALS induced apoptosis in HT29 and Caco-2 cells through mitochondrial and death receptor pathways. ALS also induced autophagy in HT29 and Caco-2 cells, with the suppression of phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR), but activation of 5' AMP-activated protein kinase (AMPK) signaling pathways. There was a differential modulating effect of ALS on p38 MAPK signaling pathway in both cell lines. Moreover, induction or inhibition of autophagy modulated basal and ALS-induced apoptosis in both cell lines. ALS potently suppressed epithelial to mesenchymal transition (EMT) in HT29 and Caco-2 cells. Collectively, it suggests that induction of cell cycle arrest, promotion of apoptosis and autophagy, and suppression of EMT involving mitochondrial, death receptor, PI3K/Akt/mTOR, p38 MAPK, and AMPK signaling pathways contribute to the cancer cell killing effect of ALS on CRC cells.
authors.affiliation: Department of Gastrointestinal Surgery, Shunde First People's Hospital Affiliated to Southern Medical University, Guangdong 528300, China. rbjsdyy@outlook.com.|Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, 12901 Bruce B. Downs Blvd., MDC 30, Tampa, FL 33612, USA. rbjsdyy@outlook.com.
authors.forename: Bao-Jun
authors.initials: BJ
authors.lastname: Ren
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, 12901 Bruce B. Downs Blvd., MDC 30, Tampa, FL 33612, USA. zzhou1@health.usf.edu.
authors.forename: Zhi-Wei
authors.initials: ZW
authors.lastname: Zhou
authors.affiliation: Department of Gastrointestinal Surgery, Shunde First People's Hospital Affiliated to Southern Medical University, Guangdong 528300, China. zdjsdyy@outlook.com.
authors.forename: Da-Jian
authors.initials: DJ
authors.lastname: Zhu
authors.affiliation: Department of Gastrointestinal Surgery, Shunde First People's Hospital Affiliated to Southern Medical University, Guangdong 528300, China. jylsdyy@outlook.com.
authors.forename: Yong-Le
authors.initials: YL
authors.lastname: Ju
authors.affiliation: Department of Gastrointestinal Surgery, Shunde First People's Hospital Affiliated to Southern Medical University, Guangdong 528300, China. wjhsdyy@outlook.com.
authors.forename: Jin-Hao
authors.initials: JH
authors.lastname: Wu
authors.affiliation: Department of Gastrointestinal Surgery, Shunde First People's Hospital Affiliated to Southern Medical University, Guangdong 528300, China. oymzsdyy@outlook.com.
authors.forename: Man-Zhao
authors.initials: MZ
authors.lastname: Ouyang
authors.affiliation: Department of Gastrointestinal Surgery, Shunde First People's Hospital Affiliated to Southern Medical University, Guangdong 528300, China. cxwsdyy@outlook.com.
authors.forename: Xiao-Wu
authors.initials: XW
authors.lastname: Chen
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, 12901 Bruce B. Downs Blvd., MDC 30, Tampa, FL 33612, USA. szhou@health.usf.edu.
authors.forename: Shu-Feng
authors.initials: SF
authors.lastname: Zhou
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D001381:Azepines / Q000494:pharmacology*; D018938:Caco-2 Cells; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D019073:HT29 Cells; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001381:Azepines; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011743:Pyrimidines; D058570:TOR Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C550258:MLN 8237; C546842:MTOR protein, human
keywords: EMT; alisertib; cell cycle; colorectal cancer; programmed cell death