Caleb C Capellen1, Jose Ortega-Rodas1, M Jane Morwitzer1,2, Hadassha M N Tofilau1, Matthew Dunworth3, Robert A Casero3, Surabhi Chandra4. 1. Department of Biology, University of Nebraska-Kearney, 2401 W. 11th Ave, BHS335, Kearney, NE, 68849, USA. 2. Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198, USA. 3. The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Bunting/Blaustein Cancer Research Building 1 1650 Orleans Street - Room 551, Baltimore, MD, 21231, USA. 4. Department of Biology, University of Nebraska-Kearney, 2401 W. 11th Ave, BHS335, Kearney, NE, 68849, USA. chandras2@unk.edu.
Abstract
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.
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.
Authors: Lan Liu; Xin Guo; Jaladanki N Rao; Tongtong Zou; Bernard S Marasa; Jie Chen; Jose Greenspon; Robert A Casero; Jian-Ying Wang Journal: Biochem J Date: 2006-09-01 Impact factor: 3.857
Authors: Adedayo A Onitilo; Rachel V Stankowski; Richard L Berg; Jessica M Engel; Ingrid Glurich; Gail M Williams; Suhail A R Doi Journal: Eur J Cancer Prev Date: 2014-03 Impact factor: 2.497
Authors: Ekaterina V Neborak; Altynay B Kaldybayeva; Lylia Bey; Aigul Y Malmakova; Anna S Tveritinova; Abdullah Hilal; Valentina K Yu; Maria V Ploskonos; Marina V Komarova; Enzo Agostinelli; Dmitry D Zhdanov Journal: Molecules Date: 2022-06-16 Impact factor: 4.927
Authors: Ehsan Irajizad; Ranran Wu; Jody Vykoukal; Eunice Murage; Rachelle Spencer; Jennifer B Dennison; Stacy Moulder; Elizabeth Ravenberg; Bora Lim; Jennifer Litton; Debu Tripathym; Vicente Valero; Senthil Damodaran; Gaiane M Rauch; Beatriz Adrada; Rosalind Candelaria; Jason B White; Abenaa Brewster; Banu Arun; James P Long; Kim Anh Do; Sam Hanash; Johannes F Fahrmann Journal: Front Artif Intell Date: 2022-08-11