<i>Let-7g</i> Upregulation Attenuated the KRAS–PI3K–Rac1–Akt Axis-Mediated Bioenergetic Functions
The aberrant activation of signaling pathways contributes to cancer cells with metabolic reprogramming. Thus, targeting signaling modulators is considered a potential therapeutic strategy for cancer. Subcellular fractionation, coimmunoprecipitation, biochemical analysis, and gene manipulation experi...
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| Format: | Article |
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MDPI AG
2023-09-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/12/18/2313 |
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| author | Kuang-Chen Hung Ni Tien Da-Tian Bau Chun-Hsu Yao Chan-Hung Chen Jiun-Long Yang Meng-Liang Lin Shih-Shun Chen |
| author_facet | Kuang-Chen Hung Ni Tien Da-Tian Bau Chun-Hsu Yao Chan-Hung Chen Jiun-Long Yang Meng-Liang Lin Shih-Shun Chen |
| author_sort | Kuang-Chen Hung |
| collection | DOAJ |
| description | The aberrant activation of signaling pathways contributes to cancer cells with metabolic reprogramming. Thus, targeting signaling modulators is considered a potential therapeutic strategy for cancer. Subcellular fractionation, coimmunoprecipitation, biochemical analysis, and gene manipulation experiments revealed that decreasing the interaction of kirsten rat sarcoma viral oncogene homolog (KRAS) with p110α in lipid rafts with the use of naringenin (NGN), a citrus flavonoid, causes lipid raft-associated phosphatidylinositol 3-kinase (PI3K)−GTP-ras-related C3 botulinum toxin substrate 1 (Rac1)−protein kinase B (Akt)-regulated metabolic dysfunction of glycolysis and mitochondrial oxidative phosphorylation (OXPHOS), leading to apoptosis in human nasopharyngeal carcinoma (NPC) cells. The use of <i>lethal-7g</i> (<i>let-7g</i>) mimic and <i>let-7g</i> inhibitor confirmed that elevated <i>let-7g</i> resulted in a decrease in KRAS expression, which attenuated the PI3K−Rac1−Akt−BCL-2/BCL-x<sub>L</sub>-modulated mitochondrial energy metabolic functions. Increased <i>let-7g</i> depends on the suppression of the RNA-specificity of monocyte chemoattractant protein-induced protein-1 (MCPIP1) ribonuclease since NGN specifically blocks the degradation of pre-let-7g by NPC cell-derived immunoprecipitated MCPIP1. Converging lines of evidence indicate that the inhibition of MCPIP1 by NGN leads to <i>let-7g</i> upregulation, suppressing oncogenic KRAS-modulated PI3K–Rac1–Akt signaling and thereby impeding the metabolic activities of aerobic glycolysis and mitochondrial OXPHOS. |
| first_indexed | 2024-03-10T22:56:43Z |
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| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T22:56:43Z |
| publishDate | 2023-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-dd9d81ac440e410cb13f2d96a3ac5a422023-11-19T10:00:16ZengMDPI AGCells2073-44092023-09-011218231310.3390/cells12182313<i>Let-7g</i> Upregulation Attenuated the KRAS–PI3K–Rac1–Akt Axis-Mediated Bioenergetic FunctionsKuang-Chen Hung0Ni Tien1Da-Tian Bau2Chun-Hsu Yao3Chan-Hung Chen4Jiun-Long Yang5Meng-Liang Lin6Shih-Shun Chen7Division of Neurosurgery, Department of Surgery, Taichung Army Force General Hospital, Taichung 41152, TaiwanDepartment of Laboratory Medicine, China Medical University Hospital, Taichung 404394, TaiwanGraduate Institute of Biomedical Sciences, China Medical University, Taichung 404333, TaiwanDepartment of Biomedical Imaging and Radiological Science, China Medical University, Taichung 404333, TaiwanDepartment of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 404333, TaiwanDepartment of Nursing, St. Mary’s Junior College of Medicine, Nursing and Management, Yilan 26644, TaiwanDepartment of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 404333, TaiwanDepartment of Medical Laboratory Science and Biotechnology, College of Medical and Health Science, Asia University, Taichung 413305, TaiwanThe aberrant activation of signaling pathways contributes to cancer cells with metabolic reprogramming. Thus, targeting signaling modulators is considered a potential therapeutic strategy for cancer. Subcellular fractionation, coimmunoprecipitation, biochemical analysis, and gene manipulation experiments revealed that decreasing the interaction of kirsten rat sarcoma viral oncogene homolog (KRAS) with p110α in lipid rafts with the use of naringenin (NGN), a citrus flavonoid, causes lipid raft-associated phosphatidylinositol 3-kinase (PI3K)−GTP-ras-related C3 botulinum toxin substrate 1 (Rac1)−protein kinase B (Akt)-regulated metabolic dysfunction of glycolysis and mitochondrial oxidative phosphorylation (OXPHOS), leading to apoptosis in human nasopharyngeal carcinoma (NPC) cells. The use of <i>lethal-7g</i> (<i>let-7g</i>) mimic and <i>let-7g</i> inhibitor confirmed that elevated <i>let-7g</i> resulted in a decrease in KRAS expression, which attenuated the PI3K−Rac1−Akt−BCL-2/BCL-x<sub>L</sub>-modulated mitochondrial energy metabolic functions. Increased <i>let-7g</i> depends on the suppression of the RNA-specificity of monocyte chemoattractant protein-induced protein-1 (MCPIP1) ribonuclease since NGN specifically blocks the degradation of pre-let-7g by NPC cell-derived immunoprecipitated MCPIP1. Converging lines of evidence indicate that the inhibition of MCPIP1 by NGN leads to <i>let-7g</i> upregulation, suppressing oncogenic KRAS-modulated PI3K–Rac1–Akt signaling and thereby impeding the metabolic activities of aerobic glycolysis and mitochondrial OXPHOS.https://www.mdpi.com/2073-4409/12/18/2313bioenergetic metabolismKRAS<i>let-7g</i>MCPIP1naringenin |
| spellingShingle | Kuang-Chen Hung Ni Tien Da-Tian Bau Chun-Hsu Yao Chan-Hung Chen Jiun-Long Yang Meng-Liang Lin Shih-Shun Chen <i>Let-7g</i> Upregulation Attenuated the KRAS–PI3K–Rac1–Akt Axis-Mediated Bioenergetic Functions Cells bioenergetic metabolism KRAS <i>let-7g</i> MCPIP1 naringenin |
| title | <i>Let-7g</i> Upregulation Attenuated the KRAS–PI3K–Rac1–Akt Axis-Mediated Bioenergetic Functions |
| title_full | <i>Let-7g</i> Upregulation Attenuated the KRAS–PI3K–Rac1–Akt Axis-Mediated Bioenergetic Functions |
| title_fullStr | <i>Let-7g</i> Upregulation Attenuated the KRAS–PI3K–Rac1–Akt Axis-Mediated Bioenergetic Functions |
| title_full_unstemmed | <i>Let-7g</i> Upregulation Attenuated the KRAS–PI3K–Rac1–Akt Axis-Mediated Bioenergetic Functions |
| title_short | <i>Let-7g</i> Upregulation Attenuated the KRAS–PI3K–Rac1–Akt Axis-Mediated Bioenergetic Functions |
| title_sort | i let 7g i upregulation attenuated the kras pi3k rac1 akt axis mediated bioenergetic functions |
| topic | bioenergetic metabolism KRAS <i>let-7g</i> MCPIP1 naringenin |
| url | https://www.mdpi.com/2073-4409/12/18/2313 |
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