title: Autophagy promotes resistance to photodynamic therapy-induced apoptosis selectively in colorectal cancer stem-like cells.
abstract: Recent studies have indicated that cancer stem-like cells (CSCs) exhibit a high resistance to current therapeutic strategies, including photodynamic therapy (PDT), leading to the recurrence and progression of colorectal cancer (CRC). In cancer, autophagy acts as both a tumor suppressor and a tumor promoter. However, the role of autophagy in the resistance of CSCs to PDT has not been reported. In this study, CSCs were isolated from colorectal cancer cells using PROM1/CD133 (prominin 1) expression, which is a surface marker commonly found on stem cells of various tissues. We demonstrated that PpIX-mediated PDT induced the formation of autophagosomes in PROM1/CD133(+) cells, accompanied by the upregulation of autophagy-related proteins ATG3, ATG5, ATG7, and ATG12. The inhibition of PDT-induced autophagy by pharmacological inhibitors and silencing of the ATG5 gene substantially triggered apoptosis of PROM1/CD133(+) cells and decreased the ability of colonosphere formation in vitro and tumorigenicity in vivo. In conclusion, our results revealed a protective role played by autophagy against PDT in CSCs and indicated that targeting autophagy could be used to elevate the PDT sensitivity of CSCs. These findings would aid in the development of novel therapeutic approaches for CSC treatment.
authors.affiliation: Institute of Biomedical Engineering; National Taiwan University; Taipei, Taiwan.
authors.forename: Ming-Feng
authors.initials: MF
authors.lastname: Wei
authors.affiliation: Department of Oncology; National Taiwan University Hospital; Taipei, Taiwan.
authors.forename: Min-Wei
authors.initials: MW
authors.lastname: Chen
authors.affiliation: Institute of Biomedical Engineering; National Taiwan University; Taipei, Taiwan; Department of Surgery; National Taiwan University Hospital; Taipei, Taiwan.
authors.forename: Ke-Cheng
authors.initials: KC
authors.lastname: Chen
authors.affiliation: Department of Otolaryngology; National Taiwan University Hospital; Taipei, Taiwan.
authors.forename: Pei-Jen
authors.initials: PJ
authors.lastname: Lou
authors.affiliation: Institute of Biomedical Engineering; National Taiwan University; Taipei, Taiwan.
authors.forename: Susan Yun-Fan
authors.initials: SY
authors.lastname: Lin
authors.affiliation: Institute of Clinical Medicine; National Yang-Ming University; Taipei, Taiwan.
authors.forename: Shih-Chieh
authors.initials: SC
authors.lastname: Hung
authors.affiliation: Genomics Research Center; Academia Sinica; Taipei, Taiwan.
authors.forename: Michael
authors.initials: M
authors.lastname: Hsiao
authors.affiliation: Gastroenterology; Taipei Medical University-Municipal Wan Fang Hospital; Taipei, Taiwan.
authors.forename: Cheng-Jung
authors.initials: CJ
authors.lastname: Yao
authors.affiliation: Institute of Biomedical Engineering; National Taiwan University; Taipei, Taiwan; Department of Oncology; National Taiwan University Hospital; Taipei, Taiwan.
authors.forename: Ming-Jium
authors.initials: MJ
authors.lastname: Shieh
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D063646:Carcinogenesis / Q000187:drug effects / Q000473:pathology; D002738:Chloroquine / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D019610:Cytoprotection / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008954:Models, Biological; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D010455:Peptides / Q000378:metabolism; D010778:Photochemotherapy; D011524:Protoporphyrins / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D011524:Protoporphyrins; D034741:RNA, Small Interfering; D002738:Chloroquine; C028025:protoporphyrin IX
keywords: apoptosis; autophagy; autophagy-related proteins; cancer stem-like cells; colonosphere; colorectal cancer; photodynamic therapy; prominin 1 (PROM1)/CD133; tumorigenicity