The growth of LNCaP, a human prostate adenocarcinoma cell line, and MCF-7, a human breast adenocarcinoma cell line, is initially hormone dependent. We previously demonstrated that LNr0-8 and MCFr0, derived from LNCaP and MCF-7 by depleting mitochondrial DNA (mtDNA), exhibited hormone-independent growth that led to progressed phenotypes. Here, we demonstrate that LNr0-8 and

Changes in mitochondrial genome such as mutation, deletion and depletion are common in cancer and can determine advanced phenotype of cancer; however, detailed mechanisms have not been elucidated. We observed that loss of mitochondrial genome reversibly induced overexpression and activation of proto-oncogenic Ras, especially K-Ras 4A, responsible for the activation of AKT and ERK leading to advanced phenotype of prostate and breast cancer. Ras activation was induced by the overexpression of 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGR), the rate-limiting enzyme of the mevalonate pathway. Hypoxia is known to induce proteasomal degradation of HMGR. Well differentiated prostate and breast cancer cells with high mitochondrial DNA content consumed a large amount of oxygen and induced hypoxia. Loss of mitochondrial genome reduced oxygen consumption and increased in oxygen concentration in the cells. The hypoxic-to-normoxic shift led to the overexpression of HMGR through inhibiting proteasomal degradation. Therefore, reduction of mitochondrial genome content induced overexpression of HMGR through hypoxic to normoxic shift and subsequently the endogenous induction of the mevalonate pathway activated Ras that mediates advanced phenotype. Reduction of mitochondrial genome content was associated with the aggressive phenotype of prostate cancer in vitro cell line model and tissue specimens in vivo. Our results elucidate a coherent mechanism that directly links the mitochondrial genome with the advanced progression of the disease.

Background In only months-to-years a primary cancer can progress to an advanced phenotype that is metastatic and resistant to clinical treatments. As early as the 1900s, it was discovered that the progression of a cancer to the advanced phenotype is often associated with a shift in the metabolic profile of the disease from a state of respiration to anaerobic fermentation – a phenomenon denoted as the Warburg Effect. Scope of Review Reports in the literature strongly suggest that the Warburg Effect is generated as a response to a loss in the integrity of the sequence and/or copy number of the mitochondrial genome content within a cancer. Multiple studies regarding the progression of cancer indicate that mutation, and/or, a flux in the copy number, of the mitochondrial genome content can support the early development of a cancer, until; the mutational load and/or the reduction-to-depletion of the copy number of the mitochondrial genome content induces the progression of the disease to an advanced phenotype. General Significance Collectively, evidence has revealed that the human cell has incorporated the mitochondrial genome content into a cellular mechanism that, when pathologically actuated, can de (un)differentiate a cancer from the parental tissue of origin into an autonomous disease that disrupts the hierarchical structure-and-function of the human body.

No abstract