Targeting Cellular Metabolism Chemosensitizes the Doxorubicin-Resistant Human Breast Adenocarcinoma Cells

Ma, Sunxiang; Jia, Rongfei; Li, Dongju; Shen, Bo

doi:10.1155/2015/453986

Cited by 24 publications

(19 citation statements)

References 16 publications

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“…The significance of glycolysis has been increasingly demonstrated in many diverse cancers, including GC. Recent studies have revealed that increased glycolysis levels possibly contribute to the development of cancer cells [48][49][50][51][52] . For example, ENO1 enhances the level of glycolysis to promote GC cells' resistance to chemotherapy 27 .…”

Section: Discussionmentioning

confidence: 99%

Enolase 1 regulates stem cell-like properties in gastric cancer cells by stimulating glycolysis

et al. 2020

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Recent studies have demonstrated that gastric cancer stem cells (CSCs) are a rare sub-group of gastric cancer (GC) cells and have an important role in promoting the tumor growth and progression of GC. In the present study, we demonstrated that the glycolytic enzyme Enolase 1 (ENO1) was involved in the regulation of the stem cell-like characteristics of GC cells, as compared to the parental cell lines PAMC-82 and SNU16, the expression of ENO1 in spheroids markedly increased. We then observed that ENO1 could enhance stem cell-like characteristics, including self-renewal capacity, cell invasion and migration, chemoresistance, and even the tumorigenicity of GC cells. ENO1 is known as an enzyme that is involved in glycolysis, but our results showed that ENO1 could markedly promote the glycolytic activity of cells. Furthermore, inhibiting glycolysis activity using 2-deoxy-d-glucose treatment significantly reduced the stemness of GC cells. Therefore, ENO1 could improve the stemness of CSCs by enhancing the cells’ glycolysis. Subsequently, to further confirm our results, we found that the inhibition of ENO1 using AP-III-a4 (ENOblock) could reduce the stemness of GC cells to a similar extent as the knockdown of ENO1 by shRNA. Finally, increased expression of ENO1 was related to poor prognosis in GC patients. Taken together, our results demonstrated that ENO1 is a significant biomarker associated with the stemness of GC cells.

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Section: Discussionmentioning

confidence: 99%

Enolase 1 regulates stem cell-like properties in gastric cancer cells by stimulating glycolysis

et al. 2020

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“…Anti-cancer treatments like radiation and chemotherapy can induce free radicals to kill cancer cells. Therefore, enhanced glycolysis may contribute to drug resistance by increasing reducing capacity [ 8 – 10 , 19 , 22 ]. In addition, the intracellular microenvironment affected by elevated glycolysis can turn to be lower glucose concentration with high levels of lactate, pyruvate and ATP, thus facilitating the development of multiple drug resistance (MDR) [ 23 – 25 ].…”

Section: Discussionmentioning

confidence: 99%

Enolase 1 stimulates glycolysis to promote chemoresistance in gastric cancer

Qian

et al. 2017

Oncotarget

106

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Chemotherapy is the major choice for the cancer treatment of early and advanced stages. However, intrinsic or acquired drug resistance significantly restricts the clinical efficacy of chemotherapy. It is critical to develop novel approaches to detect and overcome drug resistance. In this study, we demonstrated that accelerated glycolysis played a pivotal role in both intrinsic and acquired cisplatin-resistance of gastric cancer cells. The metabolic reprogramming of cisplatin-resistant cells was characterized by increased glycolysis dependence. Inhibition of glycolysis with glucose starvation or 2-Deoxy-D-glucose (2-DG) treatment significantly reversed drug resistance. By proteomic screening, we found the increased expression of the glycolytic enzyme Enolase 1 (ENO1) in cisplatin-resistant gastric cancer cells. Depletion of ENO1 by siRNA significantly reduced glycolysis and reversed drug resistance. Moreover, the increased expression of ENO1 was attributed to the down-regulation of ENO1-targeting miR-22, rather than activated gene transcriptional or prolonged protein stability. Finally, the elevated levels of ENO1 proteins were associated with the shorter overall survival of gastric cancer patients. In conclusion, ENO1 is a novel biomarker to predict drug resistance and overall prognosis in gastric cancer. Targeting ENO1 by chemical inhibitors or up-regulating miR-22 could be valuable to overcome drug resistance.

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“…As an energy-dependent transport protein, Pgp is involved in multi-drug resistance in cancer, and it further results in chemotherapy failure [ 35 ]. In the present study, immunofluorescence assay revealed that Pgp expression was significantly increased in the THC8307/Oxa cell line, but significantly decreased in both THC8307 and THC8307/Oxa cell lines after knocking-down PKM2/GLS1 expression.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of PKM2 and GLS1 expression can significantly reverse oxaliplatin-resistance in colorectal cancer cells

Lü

Lin

et al. 2017

Oncotarget

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Clinical treatment for colorectal cancer (CRC) thus far encounters a huge challenge due to oxaliplatin-resistance. As crucial rate-limiting enzymes in aerobic glycolysis and glutaminolysis, pyruvate kinase M2 type (PKM2) and kidney-type glutaminase (GLS1) are proposed to carry important implications in colorectal carcinogenesis and drug-resistance. This study aimed to explore the possible association of oxaliplatin-resistance with aerobic glycolysis/glutaminolysis indexed by PKM2/GLS1 expression. PKM2 and GLS1 expression was quantified by polymerase chain reaction (PCR) and Western blot techniques in CRC cell lines. The abilities of cell formation, kinetics, migration, invasion, survival and apoptosis, as well as permeability glycoprotein (Pgp) expression were inspected before and after knocking-down PKM2/GLS1 expression. In addition, the influence of knocking-down PKM2/GLS1 expression was evaluated in vivo. Differentiated PKM2 and GLS1 expression in both THC8307 and THC8307/Oxa cell lines was identified. In the THC8307 cell line, PKM2 and GLS1 can accelerate malignant behaviors, increase oxaliplatin-resistance, upregulate Pgp expression, and inhibit cell apoptosis. Contrastingly in the THC8307/Oxa cell line, knockdown of PKM2/GLS1 expression can restrain malignant behaviors, reestablish oxaliplatin-sensitivity, downregulate Pgp expression, and induce cell apoptosis. In xenograft, knockdown of PKM2/GLS1 expression can significantly inhibit tumor growth, reduce Pgp expression, and increase tumor apoptosis. Taken together, the present findings enriched our knowledge by demonstrating a significant association of PKM2 and GLS1 with oxaliplatin-resistance in CRC. We further propose that knockdown of PKM2/GLS1 expression may constitute a novel therapeutic strategy toward effective treatment for CRC.

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Targeting Cellular Metabolism Chemosensitizes the Doxorubicin-Resistant Human Breast Adenocarcinoma Cells

Cited by 24 publications

References 16 publications

Enolase 1 regulates stem cell-like properties in gastric cancer cells by stimulating glycolysis

Enolase 1 regulates stem cell-like properties in gastric cancer cells by stimulating glycolysis

Enolase 1 stimulates glycolysis to promote chemoresistance in gastric cancer

Knockdown of PKM2 and GLS1 expression can significantly reverse oxaliplatin-resistance in colorectal cancer cells

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