title: Doxorubicin-induced mitophagy contributes to drug resistance in cancer stem cells from HCT8 human colorectal cancer cells.
abstract: Cancer stem cells (CSCs) are known to be drug resistant. Mitophagy selectively degrades unnecessary or damaged mitochondria by autophagy during cellular stress. To investigate the potential role of mitophagy in drug resistance in CSCs, we purified CD133+/CD44+CSCs from HCT8 human colorectal cancer cells and then exposed to doxorubicin (DXR). Compared with parental cells, CSCs were more resistant to DXR treatment. Although DXR treatment enhanced autophagy levels in both cell types, the inhibition of autophagy by ATG7 silencing significantly increased the toxicity of DXR only in parental cells, not in CSCs. Interestingly, the level of mitochondrial superoxide was detected to be significantly lower in CSCs than in parental cells after DXR treatment. Furthermore, the mitophagy level and expression of BNIP3L, a mitophagy regulator, were significantly higher in CSCs than in parental cells after DXR treatment. Silencing BNIP3L significantly halted mitophagy and enhanced the sensitivity to DXR in CSCs. Our data suggested that mitophagy, but not non-selective autophagy, likely contributes to drug resistance in CSCs isolated from HCT8 cells. Further studies in other cancer cell lines will be needed to confirm our findings.
authors.affiliation: Department of Stem Cell Biology, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan.
authors.forename: Chen
authors.initials: C
authors.lastname: Yan
authors.affiliation: Department of Stem Cell Biology, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan.
authors.forename: Lan
authors.initials: L
authors.lastname: Luo
authors.affiliation: Department of Stem Cell Biology, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan; Department of Thoracic Surgery, Jiangxi Cancer Hospital, Nanchang 330029, China.
authors.forename: Chang-Ying
authors.initials: CY
authors.lastname: Guo
authors.affiliation: Department of Stem Cell Biology, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Goto
authors.affiliation: Department of Stem Cell Biology, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan.
authors.forename: Yoshishige
authors.initials: Y
authors.lastname: Urata
authors.affiliation: Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, China.
authors.forename: Jiang-Hua
authors.initials: JH
authors.lastname: Shao
authors.affiliation: Department of Stem Cell Biology, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan. Electronic address: litaoshe@nagasaki-u.ac.jp.
authors.forename: Tao-Sheng
authors.initials: TS
authors.lastname: Li
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000009:adverse effects*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism; D004317:Doxorubicin / Q000009:adverse effects*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D063306:Mitophagy / Q000235:genetics*; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D014162:Transfection
chemical_list: D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin
keywords: Autophagy; BNIP3L; Cancer stem cells; Drug resistance; Mitophagy