Abstract
The human mitochondrial ATP-dependent Lon protease functions in regulating the metabolism and quality control of proteins and mitochondrial DNA (mtDNA). However, the role of Lon in cancer is not well understood. Therefore, this study was undertaken to investigate the importance of Lon in cervical cancer cells from patients and in established cell lines. Microarray analysis from 30 cancer and 10 normal cervical tissues were analyzed by immunohistochemistry for Lon protein levels. The expression of Lon was also examined by immunoblotting 16 fresh cervical cancer tissues and their respective non-tumor cervical tissues. In all cases, Lon expression was significantly elevated in cervical carcinomas as compared to normal tissues. Augmented Lon expression in tissue microarrays did not vary between age, tumor-node-metastasis grades, or lymph node metastasis. Knocking down Lon in HeLa cervical cancer cells by lentivrial transduction resulted in a substantial decrease in both mRNA and protein levels. Such down-regulation of Lon expression significantly blocked HeLa cell proliferation. In addition, knocking down Lon resulted in decreased cellular bioenergetics as determined by measuring aerobic respiration and glycolysis using the Seahorse XF24 extracellular flux analyzer. Together, these data demonstrate that Lon plays a potential role in the oncogenesis of cervical cancer, and may be a useful biomarker and target in the treatment of cervical cancer. Lon; immunohistochemistry; cervical cancer; cell proliferation; cellular bioenergetics.
Highlights
Cervical cancer is the third most common malignancy in women worldwide, with more than 500,000 new cases diagnosed annually
Based on the notion that Lon is upregulated under stress conditions to alleviate metabolic and proteotoxic stress in cancer cells, we examined Lon expression in human cervical carcinoma tissues and normal cervical tissues using immunohistochemistry and immunoblotting and found a positive correlation between Lon overexpression and cervical cancer
We demonstrated that knocking down Lon in HeLa cervical cancer cells reduced cell proliferation, mitochondrial respiration and aerobic glycolysis
Summary
Cervical cancer is the third most common malignancy in women worldwide, with more than 500,000 new cases diagnosed annually. Human papilloma virus (HPV) infection is the most frequent risk factor in the development of most cases of cervical cancer [1,2]. Cervical cancer is potentially curable through a combination of surgery, radiation therapy, or chemotherapy. The routine use of Pap smear and HPV tests has significantly improved the outcome of cervical cancer in developed countries [3]. Despite the fact that most molecular research efforts have been based on the link between high-risk HPV types and cervical cancer, the identification of novel molecular markers and mechanisms contributing to improved diagnostic and chemotherapeutic management of this disease will be meaningful
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