TY - JOUR
T1 - Val16a sod2 polymorphism promotes epithelial–mesenchymal transition antagonized by muscadine grape skin extract in prostate cancer cells
AU - Sweeney, Janae D.
AU - Debeljak, Marija
AU - Riel, Stacy
AU - Millena, Ana Cecilia
AU - Eshleman, James R.
AU - Paller, Channing J.
AU - Odero-Marah, Valerie
N1 - Funding Information:
Funding: This research was funded by the Center for Cancer Research and Therapeutic Development at Clark Atlanta University and the National Institutes of Health (NIH)/National Institute on Minority Health and Health Disparities (NIMHD)/Research Centers in Minority Institutions Program (RCMI) Grant No. 2U54MD007590-32; NIH/National Institute of General Medical Sciences (NIGMS) Research Initiative for Scientific Enhancement (RISE) Program Grant No. 5R25GM060414-16; Greater Washington Community Foundation, Channing J. Paller.
Funding Information:
Acknowledgments: The authors would like to thank (i) the Clark Atlanta University RISE Program for funding and support, (ii) the Department of Biology at Clark Atlanta University, (iii) the Center for Cancer Research and Therapeutic Development, (iv) Channing J. Paller for her collaborative support, and (v) The Johns Hopkins University School of Medicine.
Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/2
Y1 - 2021/2
N2 - Epithelial–mesenchymal transition (EMT), a key event in cancer metastasis, allows polarized epithelial cells to assume mesenchymal morphologies, enhancing invasiveness and migration, and can be induced by reactive oxygen species (ROS). Val16A (Ala) SOD2 polymorphism has been associated with increased prostate cancer (PCa) risk. We hypothesized that SOD2 Ala single nucleotide polymorphism (SNP) may promote EMT. We analyzed SOD2 expression and genotype in various prostate cell lines. Stable overexpression of Ala-SOD2 or Val-SOD2 allele was performed in Lymph Node Carcinoma of the Prostate (LNCaP) cells followed by analysis of intracellular ROS and EMT marker protein expression. Treatments were performed with muscadine grape skin extract (MSKE) antioxidant, with or without addition of H2O2 to provide further oxidative stress. Furthermore, MTS cell proliferation, cell migration, and apoptosis assays were completed. The results showed that SOD2 expression did not correlate with tumor aggressiveness nor SOD2 genotype. We demonstrated that the Ala-SOD2 allele was associated with marked induction of EMT indicated by higher Snail and vimentin, lower E-cadherin, and increased cell migration, when compared to Val-SOD2 allele or Neo control cells. Ala-SOD2 SNP cells exhibited increased levels of total ROS and superoxide and were more sensitive to co-treatment with H2O2 and MSKE, which led to reduced cell growth and increased apoptosis. Additionally, MSKE inhibited Ala-SOD2 SNP-mediated EMT. Our data indicates that treatment with a combination of H2O2-generative drugs, such as certain chemotherapeutics and antioxidants such as MSKE that targets superoxide, hold promising therapeutic potential to halt PCa progression in the future.
AB - Epithelial–mesenchymal transition (EMT), a key event in cancer metastasis, allows polarized epithelial cells to assume mesenchymal morphologies, enhancing invasiveness and migration, and can be induced by reactive oxygen species (ROS). Val16A (Ala) SOD2 polymorphism has been associated with increased prostate cancer (PCa) risk. We hypothesized that SOD2 Ala single nucleotide polymorphism (SNP) may promote EMT. We analyzed SOD2 expression and genotype in various prostate cell lines. Stable overexpression of Ala-SOD2 or Val-SOD2 allele was performed in Lymph Node Carcinoma of the Prostate (LNCaP) cells followed by analysis of intracellular ROS and EMT marker protein expression. Treatments were performed with muscadine grape skin extract (MSKE) antioxidant, with or without addition of H2O2 to provide further oxidative stress. Furthermore, MTS cell proliferation, cell migration, and apoptosis assays were completed. The results showed that SOD2 expression did not correlate with tumor aggressiveness nor SOD2 genotype. We demonstrated that the Ala-SOD2 allele was associated with marked induction of EMT indicated by higher Snail and vimentin, lower E-cadherin, and increased cell migration, when compared to Val-SOD2 allele or Neo control cells. Ala-SOD2 SNP cells exhibited increased levels of total ROS and superoxide and were more sensitive to co-treatment with H2O2 and MSKE, which led to reduced cell growth and increased apoptosis. Additionally, MSKE inhibited Ala-SOD2 SNP-mediated EMT. Our data indicates that treatment with a combination of H2O2-generative drugs, such as certain chemotherapeutics and antioxidants such as MSKE that targets superoxide, hold promising therapeutic potential to halt PCa progression in the future.
KW - Epithelial–mesenchymal transition
KW - Prostate cancer
KW - Reactive oxygen
KW - Superoxide dismutase
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U2 - 10.3390/antiox10020213
DO - 10.3390/antiox10020213
M3 - Article
C2 - 33535682
AN - SCOPUS:85100108134
SN - 2076-3921
VL - 10
SP - 1
EP - 19
JO - Antioxidants
JF - Antioxidants
IS - 2
M1 - 213
ER -