title: High expression of MnSOD promotes survival of circulating breast cancer cells and increases their resistance to doxorubicin.
abstract: Understanding the survival mechanism of metastatic cancer cells in circulation will provide new perspectives on metastasis prevention and also shed new light on metastasis-derived drug resistance. In this study, we made it feasible to detect apoptosis of circulating tumor cells (CTCs) in real-time by integrating a fluorescence resonance energy transfer (FRET)-based caspase sensor into one in vitro microfluidic circulatory system, and two in vivo models: zebrafish circulation and mouse lung metastatic model. Our study demonstrated that fluid shear stresses triggered apoptosis of breast cancer cells in circulation by elevating the mitochondrial production of the primary free radical, superoxide anion. Cancer cells with high levels of manganese superoxide dismutase (MnSOD) exhibited stronger resistance to shear force-induced apoptosis and formed more lung metastases in mice. These metastasized cells further displayed higher resistance to chemotherapeutic agent doxorubicin, which also generates superoxide in mitochondria. Specific siRNA-mediated MnSOD knockdown reversed all three phenotypes. Our findings therefore suggest that MnSOD plays an important integrative role in supporting cancer cell survival in circulation, metastasis, and doxorubicin resistance. MnSOD can serve as a new biomarker for identifying metastatic CTCs and a novel therapeutic target for inhibiting metastasis and destroying doxorubicin-resistant breast cancer cells.
authors.affiliation: School of Chemical and Biomedical Engineering, Nanyang Technological University, Singapore.
authors.forename: Afu
authors.initials: A
authors.lastname: Fu
authors.affiliation: School of Chemical and Biomedical Engineering, Nanyang Technological University, Singapore.
authors.forename: Shijun
authors.initials: S
authors.lastname: Ma
authors.affiliation: School of Chemical and Biomedical Engineering, Nanyang Technological University, Singapore.
authors.forename: Na
authors.initials: N
authors.lastname: Wei
authors.affiliation: School of Chemical and Biomedical Engineering, Nanyang Technological University, Singapore.
authors.forename: Blanche Xiao Xuan
authors.initials: BX
authors.lastname: Tan
authors.affiliation: Department of General Surgery, Tan Tock Seng Hospital, Singapore.
authors.forename: Ern Yu
authors.initials: EY
authors.lastname: Tan
authors.affiliation: Faculty of Health Sciences, University of Macau, Taipa, Macau, China.
authors.forename: Kathy Qian
authors.initials: KQ
authors.lastname: Luo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D005260:Female; D005609:Free Radicals; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D044085:Microfluidics; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009360:Neoplastic Cells, Circulating / Q000378:metabolism*; D010641:Phenotype; D033081:Shear Strength; D013482:Superoxide Dismutase / Q000378:metabolism*; D015027:Zebrafish
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D005609:Free Radicals; D004317:Doxorubicin; D013482:Superoxide Dismutase
keywords: MnSOD; apoptosis; breast cancer metastasis; circulating tumor cells; doxorubicin resistance