title: Autophagy contributes to 4-Amino-2-Trifluoromethyl-Phenyl Retinate-induced differentiation in human acute promyelocytic leukemia NB4 cells.
abstract: As a classic differentiation agent, all-trans retinoic acid (ATRA) has been widely used in treatment of acute promyelocytic leukemia (APL). However, clinical application of ATRA has limitations. Our previous studies suggested that 4-Amino-2-Trifluoromethyl-Phenyl Retinate (ATPR), a novel all-trans retinoic acid (ATRA) derivative designed and synthesized by our team, could induce differentiation of APL cells in vivo and in vitro. To explore the underlying mechanism of ATPR, the effect of ATPR on autophagy of APL cells was observed in the present study. The results showed that the differentiation effect of ATPR on APL cells was accompanied with autophagy induction and PML-RARα degradation via activating Notch1 signaling pathway. Moreover, inhibition of autophagy using 3-methyladenine (3-MA) or small interfering RNA (siRNA) that targets essential autophagy gene ATG5 abrogated the ATPR-induced cell differentiation. Furthermore, when pretreated with DAPT, a γ-secretase inhibitor, the Notch1 signaling pathway was blocked in APL cells, followed by the reduction of ATPR-induced autophagy and differentiation. Taken together, these results suggested that autophagy play an important role in ATPR-induced cell differentiation, which may provide a novel approach to cure APL patients.
authors.affiliation: Anhui Key Laboratory of Bioactivity of Natural Products, School of Pharmacy, Anhui Medical University, Hefei, Anhui Province 230032, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Li
authors.affiliation: Anhui Key Laboratory of Bioactivity of Natural Products, School of Pharmacy, Anhui Medical University, Hefei, Anhui Province 230032, China.
authors.forename: Ge
authors.initials: G
authors.lastname: Li
authors.affiliation: Anhui Key Laboratory of Bioactivity of Natural Products, School of Pharmacy, Anhui Medical University, Hefei, Anhui Province 230032, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Wang
authors.affiliation: Anhui Key Laboratory of Bioactivity of Natural Products, School of Pharmacy, Anhui Medical University, Hefei, Anhui Province 230032, China.
authors.forename: Ya-Ya
authors.initials: YY
authors.lastname: Xie
authors.affiliation: Anhui Key Laboratory of Bioactivity of Natural Products, School of Pharmacy, Anhui Medical University, Hefei, Anhui Province 230032, China.
authors.forename: Ren-Peng
authors.initials: RP
authors.lastname: Zhou
authors.affiliation: Anhui Key Laboratory of Bioactivity of Natural Products, School of Pharmacy, Anhui Medical University, Hefei, Anhui Province 230032, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Meng
authors.affiliation: Anhui Key Laboratory of Bioactivity of Natural Products, School of Pharmacy, Anhui Medical University, Hefei, Anhui Province 230032, China.
authors.forename: Ran
authors.initials: R
authors.lastname: Ding
authors.affiliation: Anhui Key Laboratory of Bioactivity of Natural Products, School of Pharmacy, Anhui Medical University, Hefei, Anhui Province 230032, China.
authors.forename: Jin-Fang
authors.initials: JF
authors.lastname: Ge
authors.affiliation: Anhui Key Laboratory of Bioactivity of Natural Products, School of Pharmacy, Anhui Medical University, Hefei, Anhui Province 230032, China. Electronic address: cfhchina@sohu.com.
authors.forename: Fei-Hu
authors.initials: FH
authors.lastname: Chen
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects* / Q000502:physiology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy / Q000473:pathology*; D012176:Retinoids / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: C585745:4-amino-2-trifluoromethyl-phenyl retinate; D000970:Antineoplastic Agents; D012176:Retinoids
keywords: APL; ATPR; Autophagy; Differentiation