Knockdown of PGM1 enhances anticancer effects of orlistat in gastric cancer under glucose deprivation
Abstract Background Phosphoglucomutase 1 (PGM1) acts as an important regulator in glucose metabolism. However, the role of PGM1 in gastric cancer (GC) remains unclear. This study aims to investigate the role of PGM1 and develop novel regimens based on metabolic reprogramming in GC. Methods Correlati...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2021-09-01
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| Series: | Cancer Cell International |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12935-021-02193-3 |
| _version_ | 1818647740106670080 |
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| author | Bo Cao Huan Deng Hao Cui Ruiyang Zhao Hanghang Li Bo Wei Lin Chen |
| author_facet | Bo Cao Huan Deng Hao Cui Ruiyang Zhao Hanghang Li Bo Wei Lin Chen |
| author_sort | Bo Cao |
| collection | DOAJ |
| description | Abstract Background Phosphoglucomutase 1 (PGM1) acts as an important regulator in glucose metabolism. However, the role of PGM1 in gastric cancer (GC) remains unclear. This study aims to investigate the role of PGM1 and develop novel regimens based on metabolic reprogramming in GC. Methods Correlation and enrichment analyses of PGM1 were conducted based on The Cancer Genome Atlas database. Data derived from the Kaplan–Meier Plotter database were analyzed to evaluate correlations between PGM1 expression and survival time of GC patients. Cell counting kit-8, 5-Ethynyl-2-deoxyuridine, flow cytometry assays, generation of subcutaneous tumor and lung metastasis mouse models were used to determine growth and metastasis in vitro and in vivo. Cell glycolysis was detected by a battery of glycolytic indicators, including lactate, pyruvic acid, ATP production and glucose uptake. Fatty Acid Synthase (FASN) activity and expression levels of lipid enzymes were determined to reflect on lipid metabolism. Results Correlation and enrichment analyses suggested that PGM1 was closely associated with cell viability, proliferation and metabolism. PGM1 was overexpressed in GC tissues and cell lines. High PGM1 expression served as an indicator of shorter survival for specific subpopulation of GC patients. It was also correlated with pathological tumor stage and pathological tumor node metastasis stage of GC. Under the glucose deprivation condition, knockdown of PGM1 significantly suppressed cell viability, proliferation and glycolysis, whereas lipid metabolism was enhanced. Orlistat, as a drug that was designed to inhibit FASN activity, effectively induced apoptosis and suppressed lipid metabolism in GC. However, orlistat conversely increased glycolytic levels. Orlistat exhibited more significant inhibitive effects on GC progression after knockdown of PGM1 under glucose deprivation due to combination of glycolysis and lipid metabolism both in vitro and in vivo. Conclusions Downregulation of PGM1 expression under glucose deprivation enhanced anti-cancer effects of orlistat. This combination application may serve as a novel strategy for GC treatment. |
| first_indexed | 2024-12-17T01:07:20Z |
| format | Article |
| id | doaj.art-bc231753be8d40159be3aa63331cd73d |
| institution | Directory Open Access Journal |
| issn | 1475-2867 |
| language | English |
| last_indexed | 2024-12-17T01:07:20Z |
| publishDate | 2021-09-01 |
| publisher | BMC |
| record_format | Article |
| series | Cancer Cell International |
| spelling | doaj.art-bc231753be8d40159be3aa63331cd73d2022-12-21T22:09:15ZengBMCCancer Cell International1475-28672021-09-0121111510.1186/s12935-021-02193-3Knockdown of PGM1 enhances anticancer effects of orlistat in gastric cancer under glucose deprivationBo Cao0Huan Deng1Hao Cui2Ruiyang Zhao3Hanghang Li4Bo Wei5Lin Chen6Medical School of Chinese PLAMedical School of Chinese PLASchool of Medicine, Nankai UniversityMedical School of Chinese PLAMedical School of Chinese PLAMedical School of Chinese PLAMedical School of Chinese PLAAbstract Background Phosphoglucomutase 1 (PGM1) acts as an important regulator in glucose metabolism. However, the role of PGM1 in gastric cancer (GC) remains unclear. This study aims to investigate the role of PGM1 and develop novel regimens based on metabolic reprogramming in GC. Methods Correlation and enrichment analyses of PGM1 were conducted based on The Cancer Genome Atlas database. Data derived from the Kaplan–Meier Plotter database were analyzed to evaluate correlations between PGM1 expression and survival time of GC patients. Cell counting kit-8, 5-Ethynyl-2-deoxyuridine, flow cytometry assays, generation of subcutaneous tumor and lung metastasis mouse models were used to determine growth and metastasis in vitro and in vivo. Cell glycolysis was detected by a battery of glycolytic indicators, including lactate, pyruvic acid, ATP production and glucose uptake. Fatty Acid Synthase (FASN) activity and expression levels of lipid enzymes were determined to reflect on lipid metabolism. Results Correlation and enrichment analyses suggested that PGM1 was closely associated with cell viability, proliferation and metabolism. PGM1 was overexpressed in GC tissues and cell lines. High PGM1 expression served as an indicator of shorter survival for specific subpopulation of GC patients. It was also correlated with pathological tumor stage and pathological tumor node metastasis stage of GC. Under the glucose deprivation condition, knockdown of PGM1 significantly suppressed cell viability, proliferation and glycolysis, whereas lipid metabolism was enhanced. Orlistat, as a drug that was designed to inhibit FASN activity, effectively induced apoptosis and suppressed lipid metabolism in GC. However, orlistat conversely increased glycolytic levels. Orlistat exhibited more significant inhibitive effects on GC progression after knockdown of PGM1 under glucose deprivation due to combination of glycolysis and lipid metabolism both in vitro and in vivo. Conclusions Downregulation of PGM1 expression under glucose deprivation enhanced anti-cancer effects of orlistat. This combination application may serve as a novel strategy for GC treatment.https://doi.org/10.1186/s12935-021-02193-3Gastric cancerPhosphoglucomutase 1OrlistatGlucose deprivationCancer metabolismApoptosis |
| spellingShingle | Bo Cao Huan Deng Hao Cui Ruiyang Zhao Hanghang Li Bo Wei Lin Chen Knockdown of PGM1 enhances anticancer effects of orlistat in gastric cancer under glucose deprivation Cancer Cell International Gastric cancer Phosphoglucomutase 1 Orlistat Glucose deprivation Cancer metabolism Apoptosis |
| title | Knockdown of PGM1 enhances anticancer effects of orlistat in gastric cancer under glucose deprivation |
| title_full | Knockdown of PGM1 enhances anticancer effects of orlistat in gastric cancer under glucose deprivation |
| title_fullStr | Knockdown of PGM1 enhances anticancer effects of orlistat in gastric cancer under glucose deprivation |
| title_full_unstemmed | Knockdown of PGM1 enhances anticancer effects of orlistat in gastric cancer under glucose deprivation |
| title_short | Knockdown of PGM1 enhances anticancer effects of orlistat in gastric cancer under glucose deprivation |
| title_sort | knockdown of pgm1 enhances anticancer effects of orlistat in gastric cancer under glucose deprivation |
| topic | Gastric cancer Phosphoglucomutase 1 Orlistat Glucose deprivation Cancer metabolism Apoptosis |
| url | https://doi.org/10.1186/s12935-021-02193-3 |
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