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: Ming-Feng Wei, Min-Wei Chen, Ke-Cheng Chen, Pei-Jen Lou, Susan Yun-Fan Lin, Shih-Chieh Hung, Michael Hsiao, Cheng-Jung Yao, Ming-Jium Shieh
• Journal: Autophagy (Autophagy) Vol. 10 Issue 7 Pg. 1179-92 (Jul 2014) ISSN: 1554-8635 [Electronic] United States
• PMID: 24905352 (Publication Type: Journal Article)

Chemical References

• AC133 Antigen
• Antigens, CD
• Glycoproteins
• PROM1 protein, human
• Peptides
• Prom1 protein, mouse
• Protoporphyrins
• RNA, Small Interfering
• Chloroquine
• protoporphyrin IX

Topics

• AC133 Antigen
• Animals
• Antigens, CD (metabolism)
• Apoptosis (drug effects)
• Autophagy (drug effects)
• Carcinogenesis (drug effects, pathology)
• Chloroquine (pharmacology)
• Colorectal Neoplasms (drug therapy, pathology)
• Cytoprotection (drug effects)
• Drug Resistance, Neoplasm (drug effects)
• Gene Silencing (drug effects)
• Glycoproteins (metabolism)
• Humans
• Mice, Inbred NOD
• Mice, SCID
• Models, Biological
• Neoplastic Stem Cells (drug effects, metabolism, pathology)
• Peptides (metabolism)
• Photochemotherapy
• Protoporphyrins (pharmacology)
• RNA, Small Interfering (metabolism)
• Xenograft Model Antitumor Assays