Abstract
Reducing mtDNA content was considered as a critical step in the metabolism restructuring for cell stemness restoration and further neoplastic development. However, the connections between mtDNA depletion and metabolism reprograming-based cancer cell stemness in prostate cancers are still lack of studies. Here, we demonstrated that human CRPC cell line PC3 tolerated high concentration of the mtDNA replication inhibitor ethidium bromide (EtBr) and the mtDNA depletion triggered a universal metabolic remodeling process. Failure in completing that process caused lethal consequences. The mtDNA depleted (MtDP) PC3 cells could be steadily maintained in the special medium in slow cycling status. The MtDP PC3 cells contained immature mitochondria and exhibited Warburg effect. Furthermore, the MtDP PC3 cells were resistant to therapeutic treatments and contained greater cancer stem cell-like subpopulations: CD44+, ABCG2+, side-population and ALDHbright. In conclusion, these results highlight the association of mtDNA content, mitochondrial function and cancer cell stemness features.
Highlights
Prostate cancer (PCa) is the second leading cause of cancer death among men in Western countries
Only ~10% of the cells survived the treatment and initiated stable cell colonies. In this period a large number of the survived cells were found with features of epithelial-mesenchymal transition (EMT), and our realtime video suggested that the cells started to show greater mobility
There have been reports showing that mitochondrial DNA (mtDNA) depletion related mitochondrial dysfunction is associated with aggressive features in diverse tumors [39,40,41,42,43]
Summary
Prostate cancer (PCa) is the second leading cause of cancer death among men in Western countries. PCa usually begins with androgen-dependent growth with positive androgen receptor (AR+) expression, showing sensitive to androgen deprivation therapy (ADT) [2, 3]. Androgen deprivation therapy (ADT) is a common treatment for patients diagnosed with prostate cancer and this treatment can be accompanied by surgery (bilateral orchiectomy) or medical castration with luteinizing hormone-releasing hormone (LHRH) agonists. ADT with www.impactjournals.com/oncotarget anti-androgens remains as the main treatment for later stage PCa. ADT is initially effective, androgen independent prostate cancer relapse usually occurs (castration resistant prostate cancer (CRPC)) [4]. CRPC patients frequently develop metastases and therapeutic resistant properties, the main reason for treatment failure of prostate cancer patients [6,7,8,9]
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