All-trans retinoic acid downregulates ALDH1-mediated stemness and inhibits tumour formation in ovarian cancer cells.
Aldehyde dehydrogenase 1 (ALDH1) is a cancer stem-like cell (CSC) marker in human cancers; however, the specific ALDH1-regulated function and its underlying signalling pathways have not been fully demonstrated. Here, we investigated the ALDH1-regulated function and its underlying signalling and tested whether all-trans retinoic acid (ATRA) can suppress ALDH1-regulated tumour behaviour in ovarian cancer cells. By modulating ALDH1 expression using flow cytometry enrichment and exogenous overexpression or knockdown, we showed that the ALDH1 activity is positively correlated with stemness in ovarian cancer cells according to measures such as sphere formation and CSC marker expression as well as tumourigenesis in a mouse xenograft model. The findings indicate that the ALDH1 directly regulates the functions of ovarian cancer cells. We also showed that ALDH1 can regulate the expression of FoxM1 and Notch 1, which are involved in the downstream signalling of ALDH1-mediated biofunctions. Inhibition of FoxM1 by Thiostrepton and of Notch1 by DAPT downregulated the sphere formation ability of cells. ATRA reduced ALDH1 expression, suppressed tumour formation and inhibited sphere formation, cell migration and invasion in ALDH1-abundant ovarian cancer cells. We conclude that ATRA downregulates ALDH1/FoxM1/Notch1 signalling and suppresses tumour formation in ovarian cancer cells.
Institute of Basic Medical Sciences and Department of Obstetrics & Gynaecology, College of Medicine, National Cheng Kung University and Hospital, Tainan 704, Taiwan and Department of Biomedical Engineering, College of Engineering, National Cheng Kung University, Tainan 704, Taiwan.
Ming-Jer
MJ
Young
Department of Obstetrics & Gynaecology, College of Medicine, National Cheng Kung University and Hospital, Tainan 704, Taiwan and.
Yi-Hui
YH
Wu
Department of Biomedical Engineering, College of Engineering, National Cheng Kung University, Tainan 704, Taiwan.
Wen-Tai
WT
Chiu
Institute of Basic Medical Sciences and Department of Obstetrics & Gynaecology, College of Medicine, National Cheng Kung University and Hospital, Tainan 704, Taiwan and Department of Biomedical Engineering, College of Engineering, National Cheng Kung University, Tainan 704, Taiwan.
Tzu-Yu
TY
Weng
Department of Obstetrics & Gynaecology, College of Medicine, National Cheng Kung University and Hospital, Tainan 704, Taiwan and.
Yu-Fang
YF
Huang
Department of Biomedical Engineering, College of Engineering, National Cheng Kung University, Tainan 704, Taiwan chougyn@mail.ncku.edu.tw.
Cheng-Yang
CY
Chou
D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D004151:Dipeptides / Q000494:pharmacology; D015536:Down-Regulation; D005260:Female; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009361:Neoplasm Invasiveness / Q000473:pathology; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000473:pathology; D034622:RNA Interference; D034741:RNA, Small Interfering; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D050697:Retinal Dehydrogenase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D018874:Spheroids, Cellular / Q000187:drug effects; D013883:Thiostrepton / Q000494:pharmacology; D014183:Transplantation, Heterologous; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004151:Dipeptides; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D007527:Isoenzymes; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; C497761:NOTCH1 protein, human; D034741:RNA, Small Interfering; D051881:Receptor, Notch1; D014212:Tretinoin; D000080924:Aldehyde Dehydrogenase 1 Family; C510223:ALDH1A1 protein, human; C515028:ALDH1A1 protein, mouse; D050697:Retinal Dehydrogenase; D013883:Thiostrepton