TY - JOUR
T1 - Hyperglycemic conditions proliferate triple negative breast cancer cells
T2 - role of ornithine decarboxylase
AU - Capellen, Caleb C.
AU - Ortega-Rodas, Jose
AU - Morwitzer, M. Jane
AU - Tofilau, Hadassha M.N.
AU - Dunworth, Matthew
AU - Casero, Robert A.
AU - Chandra, Surabhi
N1 - Funding Information:
Research reported in this publication was supported by NIH Grants: GM103427 (SC), CA204345 (RAC), and CA235863 (RAC). In addition, funding was received from Nebraska Research Initiative Collaborative Seed Grant (SC), and Samuel Waxman Cancer Research Foundation (RAC). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Cell culture facility and fluorescence microscopy facilities at UNK were supported by grants from the National Institute for General Medical Science (NIGMS) (5P20GM103427), a component of the National Institutes of Health (NIH), as well as Nebraska Research Initiative. HT was supported as graduate research assistant through financial support provided by the Division of Research and the Office of Graduate Studies and Academic Outreach at University of Nebraska at Kearney.
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
PY - 2021/11
Y1 - 2021/11
N2 - Purpose: Several cancer subtypes (pancreatic, breast, liver, and colorectal) rapidly advance to higher aggressive stages in diabetes. Though hyperglycemia has been considered as a fuel for growth of cancer cells, pathways leading to this condition are still under investigation. Cellular polyamines can modulate normal and cancer cell growth, and inhibitors of polyamine synthesis have been approved for treating colon cancer, however the role of polyamines in diabetes-mediated cancer advancement is unclear as yet. We hypothesized that polyamine metabolic pathway is involved with increased proliferation of breast cancer cells under high glucose (HG) conditions. Methods: Studies were performed with varying concentrations of glucose (5–25 mM) exposure in invasive, triple negative breast cancer cells, MDA-MB-231; non-invasive, estrogen/progesterone receptor positive breast cancer cells, MCF-7; and non-tumorigenic mammary epithelial cells, MCF-10A. Results: There was a significant increase in proliferation with HG (25 mM) at 48–72 h in both MDA-MB-231 and MCF-10A cells but no such effect was observed in MCF-7 cells. This was correlated to higher activity of ornithine decarboxylase (ODC), a rate-limiting enzyme in polyamine synthesis pathway. Inhibitor of polyamine synthesis (difluoromethylornithine, DFMO, 5 mM) was quite effective in suppressing HG-mediated cell proliferation and ODC activity in MDA-MB-231 and MCF-10A cells. Polyamine (putrescine) levels were significantly elevated with HG treatment in MDA-MB-231 cells. HG exposure also increased the metastasis of MDA-MB-231 cells. Conclusions: Our cellular findings indicate that polyamine inhibition should be explored in patient population as a target for future chemotherapeutics in diabetic breast cancer.
AB - Purpose: Several cancer subtypes (pancreatic, breast, liver, and colorectal) rapidly advance to higher aggressive stages in diabetes. Though hyperglycemia has been considered as a fuel for growth of cancer cells, pathways leading to this condition are still under investigation. Cellular polyamines can modulate normal and cancer cell growth, and inhibitors of polyamine synthesis have been approved for treating colon cancer, however the role of polyamines in diabetes-mediated cancer advancement is unclear as yet. We hypothesized that polyamine metabolic pathway is involved with increased proliferation of breast cancer cells under high glucose (HG) conditions. Methods: Studies were performed with varying concentrations of glucose (5–25 mM) exposure in invasive, triple negative breast cancer cells, MDA-MB-231; non-invasive, estrogen/progesterone receptor positive breast cancer cells, MCF-7; and non-tumorigenic mammary epithelial cells, MCF-10A. Results: There was a significant increase in proliferation with HG (25 mM) at 48–72 h in both MDA-MB-231 and MCF-10A cells but no such effect was observed in MCF-7 cells. This was correlated to higher activity of ornithine decarboxylase (ODC), a rate-limiting enzyme in polyamine synthesis pathway. Inhibitor of polyamine synthesis (difluoromethylornithine, DFMO, 5 mM) was quite effective in suppressing HG-mediated cell proliferation and ODC activity in MDA-MB-231 and MCF-10A cells. Polyamine (putrescine) levels were significantly elevated with HG treatment in MDA-MB-231 cells. HG exposure also increased the metastasis of MDA-MB-231 cells. Conclusions: Our cellular findings indicate that polyamine inhibition should be explored in patient population as a target for future chemotherapeutics in diabetic breast cancer.
KW - Breast cancer
KW - Diabetes
KW - High glucose
KW - Ornithine decarboxylase
KW - Polyamine
KW - Putrescine
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U2 - 10.1007/s10549-021-06388-0
DO - 10.1007/s10549-021-06388-0
M3 - Article
C2 - 34529197
AN - SCOPUS:85114927923
SN - 0167-6806
VL - 190
SP - 255
EP - 264
JO - Breast Cancer Research and Treatment
JF - Breast Cancer Research and Treatment
IS - 2
ER -