Abstract
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-rasG12D (HPNE/K-rasG12D) and human embryonic kidney cells with tetracycline repressorT-Rex/K-rasG12V, 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.
Highlights
Mutations in KRAS gene are cancer-driven genetic events that are often seen in pancreatic ductal adenocarcinoma (90%) [1,2], lung [3], and colon [4] cancers (30–40%)
We have previously shown that K-ras (G12V) activation led to mitochondrial dysfunction, manifested by a decrease in oxygen consumption and an increase in generation of reactive oxygen species (ROS) [7,8]
Our previous study showed that activation of K-ras led to mitochondrial dysfunction [7,9], we first used two doxycycline-inducible K-ras expression cell models, HPNE/K-rasG12D and T-Rex/K-rasG12V, to test the potential effect of oncogenic K-ras on the expression of candidate genes involved in regulation of mitochondrial function and morphology
Summary
Mutations in KRAS gene are cancer-driven genetic events that are often seen in pancreatic ductal adenocarcinoma (90%) [1,2], lung [3], and colon [4] cancers (30–40%). Mitochondrial dysfunction and metabolic alterations may contribute to the highly malignant phenotype of K-ras-driven cells. We have previously shown that K-ras (G12V) activation led to mitochondrial dysfunction, manifested by a decrease in oxygen consumption and an increase in generation of reactive oxygen species (ROS) [7,8]. Activation of K-ras could induce a decrease in NDUFAF1 expression leading to mitochondrial dysfunction and an increased generation of ROS
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