Journal
ONCOTARGET
Volume 5, Issue 22, Pages 11209-11224Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.2026
Keywords
mitochondria; protein quality control; Lon protease; bladder cancer; chemosensitivity; cellular bioenergetics
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Funding
- National Natural Science Foundation of China [31070710, 31171345]
- National Basic Research Program of China (973 Program) [2013CB531700]
- Zhejiang Qianjiang Talent Project B [2010R10045]
- Wenzhou Medical University Foundation [QTJ09010]
- Scientific Research Foundation for the Returned Overseas Chinese Scholar, State Education Ministry
- Natural Science Foundation of Zhejiang Province [Y2110097]
- Key Science and Technology Innovation Team of Zhejiang Province [2010R50048]
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ATP-dependent Lon protease within mitochondrial matrix contributes to the degradation of abnormal proteins. The oxidative or hypoxic stress which represents the stress phenotype of cancer leads to up-regulation of Lon. However, the role of Lon in bladder cancer remains undefined. Here, we found that Lon expression in bladder cancer tissues was significantly higher than those in noncancerous tissues; down-regulation of Lon in bladder cancer cells significantly blocked cancer cell proliferation via suppression c-Jun N-terminal kinase (JNK) phosphorylation due to decreased reactive oxygen species (ROS) production and enhanced the sensitivity of bladder cancer cells to chemotherapeutic agents by promoting apoptosis. We further found that Lon down-regulation in bladder cancer cells decreased cellular bioenergetics as determined by measuring aerobic respiration and glycolysis using extracellular flux analyzer. The tissue microarray (TMA) results showed that high expression of Lon was related to the T and TNM stage, as well as histological grade of bladder cancer patients. We also demonstrated that Lon was an independent prognostic factor for overall survival of bladder cancer patients. Taken together, our data suggest that Lon could serve as a potential diagnostic biomarker and therapeutic target for treatment of bladder cancer, as well as for prediction of the effectiveness of chemotherapy.
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