Nuclear translocation of Atox1 potentiates activin A-induced cell migration and colony formation in colon cancer


Autoři: Arundhati Jana aff001;  Archita Das aff002;  Nancy L. Krett aff001;  Grace Guzman aff003;  Alexandra Thomas aff001;  Georgina Mancinelli aff001;  Jessica Bauer aff001;  Masuko Ushio-Fukai aff004;  Tohru Fukai aff002;  Barbara Jung aff001
Působiště autorů: Division of Gastroenterology and Hepatology, University of Illinois Medical College, Chicago, IL, United States of America aff001;  Vascular Biology Center, Department of Pharmacology and Toxicology, Medical College of Georgia at Augusta University, Augusta, GA, United States of America aff002;  Department of Pathology, University of Illinois Medical College, Chicago, IL, United States of America aff003;  Vascular Biology Center, Department of Medicine (Cardiology), Medical College of Georgia at Augusta University, Augusta, GA, United States of America aff004;  Charlie Norwood Veterans Affairs Medical Center, Augusta, GA, United States of America aff005
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article
doi: 10.1371/journal.pone.0227916

Souhrn

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.

Klíčová slova:

Cancer cell migration – Cancer treatment – Colon – Colorectal cancer – Cyclins – Metastasis – Nuclear staining – SW480 cells


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