Oncogenic K-ras Induces Mitochondrial OPA3 Expression to Promote Energy Metabolism in Pancreatic Cancer Cells
K-ras (Kirsten ras GTPase) mutations are oncogenic events frequently observed in many cancer types especially in pancreatic cancer. Although mitochondrial dysfunction has been associated with K-ras mutation, the molecular mechanisms by which K-ras impacts mitochondria and maintains metabolic homeost...
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| Format: | Article |
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MDPI AG
2019-12-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/12/1/65 |
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| author | Ning Meng Christophe Glorieux Yanyu Zhang Liyun Liang Peiting Zeng Wenhua Lu Peng Huang |
| author_facet | Ning Meng Christophe Glorieux Yanyu Zhang Liyun Liang Peiting Zeng Wenhua Lu Peng Huang |
| author_sort | Ning Meng |
| collection | DOAJ |
| description | K-ras (Kirsten ras GTPase) mutations are oncogenic events frequently observed in many cancer types especially in pancreatic cancer. Although mitochondrial dysfunction has been associated with K-ras mutation, the molecular mechanisms by which K-ras impacts mitochondria and maintains metabolic homeostasis are not fully understood. In this study, we used two K-ras inducible cell systems, human pancreatic epithelial/ K-ras<sup>G12D</sup> (HPNE/K-ras<sup>G12D</sup>) and human embryonic kidney cells with tetracycline repressorT-Rex/K-ras<sup>G12V</sup>, to evaluate the role of oncogenic K-ras in regulating mitochondrial function. Among a panel of genes known to affect mitochondria, only the expression of OPA3 (optic atrophy protein 3) was consistently up-regulated by K-ras activation in both cell lines. Importantly, high expression of OPA3 was also observed in clinical pancreatic cancer tissues. Genetic knockdown of OPA3 caused a significant decrease of energy metabolism, manifested by a suppression of oxygen consumption rate (OCR) and a decrease in cellular ATP content, leading to inhibition of cell proliferation capacity and reduced expression of epithelial−mesenchymal transition (EMT) markers. Our study suggests that OPA3 may promote cellular energy metabolism and its up-regulation in K-ras-driven cancer is likely a mechanism to offset the negative impact of K-ras on mitochondria to maintain energy homeostasis. As such, OPA3 could be a potential target to kill cancer cells with K-ras mutations. |
| first_indexed | 2024-03-12T10:19:52Z |
| format | Article |
| id | doaj.art-a433f2f22cb5446d9eceb892fc6e4182 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T10:19:52Z |
| publishDate | 2019-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-a433f2f22cb5446d9eceb892fc6e41822023-09-02T10:11:08ZengMDPI AGCancers2072-66942019-12-011216510.3390/cancers12010065cancers12010065Oncogenic K-ras Induces Mitochondrial OPA3 Expression to Promote Energy Metabolism in Pancreatic Cancer CellsNing Meng0Christophe Glorieux1Yanyu Zhang2Liyun Liang3Peiting Zeng4Wenhua Lu5Peng Huang6Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, ChinaSun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, ChinaSun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, ChinaSun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, ChinaSun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, ChinaSun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, ChinaSun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, ChinaK-ras (Kirsten ras GTPase) mutations are oncogenic events frequently observed in many cancer types especially in pancreatic cancer. Although mitochondrial dysfunction has been associated with K-ras mutation, the molecular mechanisms by which K-ras impacts mitochondria and maintains metabolic homeostasis are not fully understood. In this study, we used two K-ras inducible cell systems, human pancreatic epithelial/ K-ras<sup>G12D</sup> (HPNE/K-ras<sup>G12D</sup>) and human embryonic kidney cells with tetracycline repressorT-Rex/K-ras<sup>G12V</sup>, to evaluate the role of oncogenic K-ras in regulating mitochondrial function. Among a panel of genes known to affect mitochondria, only the expression of OPA3 (optic atrophy protein 3) was consistently up-regulated by K-ras activation in both cell lines. Importantly, high expression of OPA3 was also observed in clinical pancreatic cancer tissues. Genetic knockdown of OPA3 caused a significant decrease of energy metabolism, manifested by a suppression of oxygen consumption rate (OCR) and a decrease in cellular ATP content, leading to inhibition of cell proliferation capacity and reduced expression of epithelial−mesenchymal transition (EMT) markers. Our study suggests that OPA3 may promote cellular energy metabolism and its up-regulation in K-ras-driven cancer is likely a mechanism to offset the negative impact of K-ras on mitochondria to maintain energy homeostasis. As such, OPA3 could be a potential target to kill cancer cells with K-ras mutations.https://www.mdpi.com/2072-6694/12/1/65k-rasmitochondriaopa3pancreatic cancerenergy metabolism |
| spellingShingle | Ning Meng Christophe Glorieux Yanyu Zhang Liyun Liang Peiting Zeng Wenhua Lu Peng Huang Oncogenic K-ras Induces Mitochondrial OPA3 Expression to Promote Energy Metabolism in Pancreatic Cancer Cells Cancers k-ras mitochondria opa3 pancreatic cancer energy metabolism |
| title | Oncogenic K-ras Induces Mitochondrial OPA3 Expression to Promote Energy Metabolism in Pancreatic Cancer Cells |
| title_full | Oncogenic K-ras Induces Mitochondrial OPA3 Expression to Promote Energy Metabolism in Pancreatic Cancer Cells |
| title_fullStr | Oncogenic K-ras Induces Mitochondrial OPA3 Expression to Promote Energy Metabolism in Pancreatic Cancer Cells |
| title_full_unstemmed | Oncogenic K-ras Induces Mitochondrial OPA3 Expression to Promote Energy Metabolism in Pancreatic Cancer Cells |
| title_short | Oncogenic K-ras Induces Mitochondrial OPA3 Expression to Promote Energy Metabolism in Pancreatic Cancer Cells |
| title_sort | oncogenic k ras induces mitochondrial opa3 expression to promote energy metabolism in pancreatic cancer cells |
| topic | k-ras mitochondria opa3 pancreatic cancer energy metabolism |
| url | https://www.mdpi.com/2072-6694/12/1/65 |
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