Abstract
Metastatic competence of cancer cells is influenced by many factors including metabolic alterations and changes in mitochondrial biogenesis and protein homeostasis. While it is generally accepted that mitochondria play important roles in tumorigenesis, the respective molecular events that regulate aberrant cancer cell proliferation remain to be clarified. Therefore, understanding the mechanisms underlying the role of mitochondria in cancer progression has potential implications in the development of new therapeutic strategies. We show that low expression of mitochondrial quality control protease OMA1 correlates with poor overall survival in breast cancer patients. Silencing OMA1 in vitro in patient-derived metastatic breast cancer cells isolated from the metastatic pleural effusion and atypical ductal hyperplasia mammary tumor specimens (21MT-1 and 21PT) enhances the formation of filopodia, increases cell proliferation (Ki67 expression), and induces epithelial-mesenchymal transition (EMT). Mechanistically, loss of OMA1 results in alterations in the mitochondrial protein homeostasis, as reflected by enhanced expression of canonic mitochondrial unfolded protein response genes. These changes significantly increase migratory properties in metastatic breast cancer cells, indicating that OMA1 plays a critical role in suppressing metastatic competence of breast tumors. Interestingly, these results were not observed in OMA1-depleted non-tumorigenic MCF10A mammary epithelial cells. This newly identified reduced activity/levels of OMA1 provides insights into the mechanisms leading to breast cancer development, promoting malignant progression of cancer cells and unfavorable clinical outcomes, which may represent possible prognostic markers and therapeutic targets for breast cancer treatment.
Highlights
Breast cancer is a complex disease affecting over 180,000 women annually involving a continuously changing phenotype and microenvironment leading to differences in the gene and protein profile of the neoplasm[1,2,3,4,5]
We report that depletion of Overlapping With The m-AAA Protease 1 (OMA1) in stable, patient-derived breast cancer cells isolated from the metastatic pleural effusion (21MT-1) and atypical ductal hyperplasia (21PT) increased expression of the canonical mitochondrial unfolded protein response (UPRmt) markers, cell spreading, and filopodia formation
We have identified a novel role of the mitochondrial metallopeptidase OMA1 in the regulation of tumor progression in breast cancer cells
Summary
Breast cancer is a complex disease affecting over 180,000 women annually involving a continuously changing phenotype and microenvironment leading to differences in the gene and protein profile of the neoplasm[1,2,3,4,5]. Mounting evidence indicates that altered mitochondrial functions play a significant role(s) in the regulation of tumor cell biology and are likely involved in tumor progression including metastasis[7,8,9,10,11,12]. Many cancer cells undergo the metabolic adaptation known as aerobic glycolysis, or Warburg effect; which involves enhanced utilization of glucose or pyruvate for anabolic processes underpinning rapid proliferation[12,13,14]. Elevated activities of ATP-driven proteases Lon proteases (LONP) and mitochondrial unfoldase-peptidase complex ClpXP have been shown to correlate with tumor development and progression[23,24] Inhibition of these proteases has been proposed as a potential therapeutic strategy in patients with lymphoma and acute myeloid leukemia, respectively[22,25]. Together with bioinformatics data indicating that breast cancer patients with low, EMT markers-correlating OMA1 expression have a shorter survival time, our findings led us to conclude that impaired MQC function through OMA1 deficit can regulate malignancy and metastatic progression in breast cancer
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