TY - JOUR
T1 - Nuclear translocation of Atox1 potentiates activin A-induced cell migration and colony formation in colon cancer
AU - Jana, Arundhati
AU - Das, Archita
AU - Krett, Nancy L.
AU - Guzman, Grace
AU - Thomas, Alexandra
AU - Mancinelli, Georgina
AU - Bauer, Jessica
AU - Ushio-Fukai, Masuko
AU - Fukai, Tohru
AU - Jung, Barbara
N1 - Funding Information:
The research reported in this manuscript was supported by National Institutes of Health RO1 CA141057, U.S. Department of Veterans Affairs 2I01BX001232, National Heart, Lung, and Blood Institute RO1HL133613, National Heart, Lung, and Blood Institute R01HL133613, and National Heart, Lung, and Blood Institute R01HL116976. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of manuscript.
Publisher Copyright:
© 2020 Jana et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2020/1/1
Y1 - 2020/1/1
N2 - Background Colorectal cancer remains a deadly cancer due to metastatic disease. To understand the molecular mechanisms of metastasis in colon cancer, we investigated whether the copper chaperone antioxidant-1 (Atox1) protein plays a role in this process. Recent findings indicate that Atox1 protein has transcription factor activities and plays a vital role in cell proliferation in cancer cells. However, the role of Atox1 in metastasis has not been examined. Methods Atox1 expression was determined by immunofluorescence in a tissue microarray generated from a spectrum of CRC patients. Subcellular fractionation of colon cancer cell lines SW480 and SW620 cells was used to examine the cellular location of Atox1 in the face of activin A, a cytokine that stimulates colon cancer metastasis. Atox1 expression was genetically manipulated and cellular migration measured through trans-well assay and proliferation measured by colony formation assays. Results Here we demonstrate that in patients with metastatic colon cancer, there is a significant increase in the expression of nuclear Atox1. Interestingly, the metastatic CRC cell line SW620 has increased nuclear localization of Atox1 compared to its related non-metastatic cell line SW480. Further, inhibition of endogenous Atox1 by siRNA in SW620 decreased colony formation and reactive oxygen species generation via decreased expression of Atox1 targets cyclin D1 and NADPH oxidase subunit p47 phox, respectively. Additionally, overexpression of nuclear-targeted but not copper binding domain-mutated Atox1 in SW480 cells increased colony formation and cell migration that was further augmented by activin A stimulation, a known enhancer of colon cancer metastasis. Conclusions Our findings suggest that nuclear Atox1 might be a new therapeutic target as well as a new biomarker for metastatic colorectal cancer.
AB - Background Colorectal cancer remains a deadly cancer due to metastatic disease. To understand the molecular mechanisms of metastasis in colon cancer, we investigated whether the copper chaperone antioxidant-1 (Atox1) protein plays a role in this process. Recent findings indicate that Atox1 protein has transcription factor activities and plays a vital role in cell proliferation in cancer cells. However, the role of Atox1 in metastasis has not been examined. Methods Atox1 expression was determined by immunofluorescence in a tissue microarray generated from a spectrum of CRC patients. Subcellular fractionation of colon cancer cell lines SW480 and SW620 cells was used to examine the cellular location of Atox1 in the face of activin A, a cytokine that stimulates colon cancer metastasis. Atox1 expression was genetically manipulated and cellular migration measured through trans-well assay and proliferation measured by colony formation assays. Results Here we demonstrate that in patients with metastatic colon cancer, there is a significant increase in the expression of nuclear Atox1. Interestingly, the metastatic CRC cell line SW620 has increased nuclear localization of Atox1 compared to its related non-metastatic cell line SW480. Further, inhibition of endogenous Atox1 by siRNA in SW620 decreased colony formation and reactive oxygen species generation via decreased expression of Atox1 targets cyclin D1 and NADPH oxidase subunit p47 phox, respectively. Additionally, overexpression of nuclear-targeted but not copper binding domain-mutated Atox1 in SW480 cells increased colony formation and cell migration that was further augmented by activin A stimulation, a known enhancer of colon cancer metastasis. Conclusions Our findings suggest that nuclear Atox1 might be a new therapeutic target as well as a new biomarker for metastatic colorectal cancer.
UR - http://www.scopus.com/inward/record.url?scp=85078145826&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85078145826&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0227916
DO - 10.1371/journal.pone.0227916
M3 - Article
C2 - 31961892
AN - SCOPUS:85078145826
SN - 1932-6203
VL - 15
JO - PloS one
JF - PloS one
IS - 1
M1 - e0227916
ER -
