scholarly journals Functional expression of sodium-glucose transporters in cancer

2015 ◽  
Vol 112 (30) ◽  
pp. E4111-E4119 ◽  
Author(s):  
Claudio Scafoglio ◽  
Bruce A. Hirayama ◽  
Vladimir Kepe ◽  
Jie Liu ◽  
Chiara Ghezzi ◽  
...  
Keyword(s):  
Cell Survival ◽  
Glucose Uptake ◽  
Cancer Cell ◽  
Pet Imaging ◽  
Xenograft Model ◽  
Glucose Transporters ◽  
Functional Expression ◽  
Sglt2 Inhibitors ◽  
Cancer Cell Survival

Glucose is a major metabolic substrate required for cancer cell survival and growth. It is mainly imported into cells by facilitated glucose transporters (GLUTs). Here we demonstrate the importance of another glucose import system, the sodium-dependent glucose transporters (SGLTs), in pancreatic and prostate adenocarcinomas, and investigate their role in cancer cell survival. Three experimental approaches were used: (i) immunohistochemical mapping of SGLT1 and SGLT2 distribution in tumors; (ii) measurement of glucose uptake in fresh isolated tumors using an SGLT-specific radioactive glucose analog, α-methyl-4-deoxy-4-[18F]fluoro-d-glucopyranoside (Me4FDG), which is not transported by GLUTs; and (iii) measurement of in vivo SGLT activity in mouse models of pancreatic and prostate cancer using Me4FDG-PET imaging. We found that SGLT2 is functionally expressed in pancreatic and prostate adenocarcinomas, and provide evidence that SGLT2 inhibitors block glucose uptake and reduce tumor growth and survival in a xenograft model of pancreatic cancer. We suggest that Me4FDG-PET imaging may be used to diagnose and stage pancreatic and prostate cancers, and that SGLT2 inhibitors, currently in use for treating diabetes, may be useful for cancer therapy.

scholarly journals Osteoblast-Derived Paracrine and Juxtacrine Signals Protect Disseminated Breast Cancer Cells from Stress

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1366
Author(s):  
Russell Hughes ◽  
Xinyue Chen ◽  
Natasha Cowley ◽  
Penelope D. Ottewell ◽  
Rhoda J. Hawkins ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Survival ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Breast Cancer Cells ◽  
Metastatic Breast ◽  
Accessory Cell ◽  
Cancer Cell Survival

Metastatic breast cancer in bone is incurable and there is an urgent need to develop new therapeutic approaches to improve survival. Key to this is understanding the mechanisms governing cancer cell survival and growth in bone, which involves interplay between malignant and accessory cell types. Here, we performed a cellular and molecular comparison of the bone microenvironment in mouse models representing either metastatic indolence or growth, to identify mechanisms regulating cancer cell survival and fate. In vivo, we show that regardless of their fate, breast cancer cells in bone occupy niches rich in osteoblastic cells. As the number of osteoblasts in bone declines, so does the ability to sustain large numbers of breast cancer cells and support metastatic outgrowth. In vitro, osteoblasts protected breast cancer cells from death induced by cell stress and signaling via gap junctions was found to provide important juxtacrine protective mechanisms between osteoblasts and both MDA-MB-231 (TNBC) and MCF7 (ER+) breast cancer cells. Combined with mathematical modelling, these findings indicate that the fate of DTCs is not controlled through the association with specific vessel subtypes. Instead, numbers of osteoblasts dictate availability of protective niches which breast cancer cells can colonize prior to stimulation of metastatic outgrowth.

scholarly journals ATM inhibition drives metabolic adaptation via induction of macropinocytosis

2020 ◽  
Author(s):  
Chi-Wei Chen ◽  
Raquel Buj ◽  
Erika S. Dahl ◽  
Kelly E. Leon ◽  
Erika L. Varner ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Survival ◽  
Cancer Cell ◽  
Metabolic Reprogramming ◽  
Metabolic Adaptation ◽  
Dependent Manner ◽  
Cancer Cell Survival ◽  
Branched Chain

SummaryMacropinocytosis is a nonspecific endocytic process that enhances cancer cell survival under nutrient-poor conditions. Ataxia-Telangiectasia mutated (ATM) is a tumor suppressor that plays a role in cellular metabolic reprogramming. We report that suppression of ATM increases macropinocytosis in an AMPK-dependent manner to promote cancer cell survival in nutrient-poor conditions. Combined inhibition of ATM and macropinocytosis suppressed proliferation and induced cell death both in vitro and in vivo. Metabolite analysis of the ascites and interstitial fluid from tumors indicated decreased branched chain amino acids (BCAAs) in the microenvironment of ATM-inhibited tumors. Supplementation of ATM inhibitor-treated cells with BCAAs abrogated AMPK phosphorylation and macropinocytosis and rescued the cell death that occurs due to combined inhibition of ATM and macropinocytosis. These data reveal a novel molecular basis of ATM-mediated tumor suppression whereby loss of ATM promotes pro-tumorigenic uptake of nutrients to promote cancer cell survival and reveal a metabolic vulnerability of ATM-inhibited cells.

scholarly journals Molecular Mechanism for the Control of Eukaryotic Elongation Factor 2 Kinase by pH: Role in Cancer Cell Survival

2015 ◽  
Vol 35 (10) ◽  
pp. 1805-1824 ◽  
Author(s):  
Jianling Xie ◽  
Halina Mikolajek ◽  
Craig R. Pigott ◽  
Kelly J. Hooper ◽  
Toby Mellows ◽  
...  
Keyword(s):  
Cell Survival ◽  
Cancer Cell ◽  
Catalytic Domain ◽  
Elongation Factor ◽  
Cell Physiology ◽  
Elongation Factor 2 ◽  
Eukaryotic Elongation Factor 2 ◽  
Eukaryotic Elongation Factor ◽  
Cancer Cell Survival

Acidification of the extracellular and/or intracellular environment is involved in many aspects of cell physiology and pathology. Eukaryotic elongation factor 2 kinase (eEF2K) is a Ca2+/calmodulin-dependent kinase that regulates translation elongation by phosphorylating and inhibiting eEF2. Here we show that extracellular acidosis elicits activation of eEF2Kin vivo, leading to enhanced phosphorylation of eEF2. We identify five histidine residues in eEF2K that are crucial for the activation of eEF2K during acidosis. Three of them (H80, H87, and H94) are in its calmodulin-binding site, and their protonation appears to enhance the ability of calmodulin to activate eEF2K. The other two histidines (H227 and H230) lie in the catalytic domain of eEF2K. We also identify His108 in calmodulin as essential for activation of eEF2K. Acidification of cancer cell microenvironments is a hallmark of malignant solid tumors. Knocking down eEF2K in cancer cells attenuated the decrease in global protein synthesis when cells were cultured at acidic pH. Importantly, activation of eEF2K is linked to cancer cell survival under acidic conditions. Inhibition of eEF2K promotes cancer cell death under acidosis.

Co-targeting EGFR and Autophagy Impairs Ovarian Cancer Cell Survival during Detachment from the ECM

2015 ◽  
Vol 15 (3) ◽  
pp. 215-226 ◽  
Author(s):  
Zongyuan Yang ◽  
Yi Liu ◽  
Xiao Wei ◽  
Xiaoshui Zhou ◽  
Cheng Gong ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Survival ◽  
Cancer Cell ◽  
Ovarian Cancer Cell ◽  
Cancer Cell Survival
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