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...

Full description

Saved in:
Bibliographic Details
Published in:Cancers 2019-12, Vol.12 (1), p.65
Main Authors: Meng, Ning, Glorieux, Christophe, Zhang, Yanyu, Liang, Liyun, Zeng, Peiting, Lu, Wenhua, Huang, Peng
Format: Article
Language:English
Subjects:
Apoptosis
Atrophy
Biosynthesis
Cell activation
Cell growth
Cell proliferation
Cloning
Energy balance
Energy metabolism
Gene expression
Homeostasis
Kinases
Mesenchyme
Metabolism
Mitochondria
Molecular modelling
Morphology
Mutation
Optic atrophy
Oxygen consumption
Pancreatic cancer
Phosphorylation
Proteins
Respiration
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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 (HPNE/K-ras ) and human embryonic kidney cells with tetracycline repressorT-Rex/K-ras , 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.
ISSN:2072-6694
2072-6694
DOI:10.3390/cancers12010065