title: FTY720-induced enhancement of autophagy protects cells from FTY720 cytotoxicity in colorectal cancer.
abstract: FTY720, also known as fingolimod, is a widely used immunomodulator in multiple sclerosis and multiple organ transplantation. It is also an important protein phosphatase 2A (PP2A) activator. Based on this, a number of studies have recently demonstrated the cytotoxic effect of FTY720 in various cancers. Yet in colorectal cancer (CRC), the underlying mechanisms of FTY720 cytotoxicity remain less clear, especially the relationship between a drug and autophagy. We demonstrate here for the first time that FTY720 promotes the appearance of autophagic hallmarks such as autophagosome formation and light chain 3 (LC3)-II accumulation, indicating the participation of autophagy in FTY720 cytotoxicity on CRC. Moreover, inhibition of autophagy using 3-methyladenine (3-MA), a specific inhibitor of autophagy, enhanced FTY720 cytotoxicity, indicating the protective role of autophagy against the drug's own cytotoxic effect. The protective autophagy was likely affected by cancerous inhibitor of PP2A (CIP2A), an endogenous PP2A inhibitor that is closely related with poor prognosis and drug resistance. Consequently, our data not only demonstrate a new mechanism underlying the cytotoxic effect of FTY720 in CRC, but also a new strategy for CRC treatment, especially in cases resistant to conventional chemotherapies because of high CIP2A levels.
authors.affiliation: Department of Colorectal Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China.
authors.forename: Juan
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of General Surgery, Wuxi Affiliated Hospital of Nanjing University of Chinese Medicine, Wuxi, P.R. China.
authors.forename: Shu-Wei
authors.initials: SW
authors.lastname: Wang
authors.affiliation: Department of Colorectal Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China.
authors.forename: Dong-Sheng
authors.initials: DS
authors.lastname: Zhang
authors.affiliation: Department of Colorectal Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Colorectal Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China.
authors.forename: Chun-Yan
authors.initials: CY
authors.lastname: Zhu
authors.affiliation: Department of Colorectal Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Fei
authors.affiliation: Department of Hepatobiliary Surgery, First People's Hospital of Changzhou, Changzhou, Jiangsu 214000, P.R. China.
authors.forename: Jun
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Colorectal Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China.
authors.forename: Chuan
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Colorectal Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China.
authors.forename: Yue-Ming
authors.initials: YM
authors.lastname: Sun
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001324:Autoantigens / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004354:Drug Screening Assays, Antitumor; D000068876:Fingolimod Hydrochloride / Q000494:pharmacology*; D059585:G1 Phase Cell Cycle Checkpoints; D006801:Humans; D020128:Inhibitory Concentration 50; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001324:Autoantigens; C500266:CIP2A protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D054648:Protein Phosphatase 2; D000068876:Fingolimod Hydrochloride