Abstract
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.
Highlights
Mitochondria are essential organelles that generate ATP through oxidative phosphorylation. This process is accomplished by a series of protein complexes and mitochondrial respiratory chains encoded by nuclear DNA and mitochondrial DNA
Classical cell lines for the in vitro evaluation of Prostate cancer (PCa), include: the castration sensitive LNCaP established from a metastatic lesion of human prostate adenocarcinoma;[18] the castration resistant (CR) C4-2 isolated from recurrent tumors that develop after castration of mice inoculated with LNCaP;[19] and CR PCa cell lines derived from metastasis in human bone (PC-3) and brain (DU-145).[20,21]
Our collective report demonstrates in PCa that the (1) inhibition of respiration, by reduction of the mitochondrial genome content, shifts cells from a hypoxic-to-normoxic state (2) that attenuates the endogenous proteasomal degradation of the HMGR enzyme; (3) the increase in mevalonate pathway (4) induces the constitutive activation of nuclear-encoded proto-oncogenic Ras (5) that signal for an array of cancer progression signals (Figure 8b)
Summary
Mitochondria are essential organelles that generate ATP through oxidative phosphorylation. Human cancers (B25%) often harbor (oncogenic) mutations in Ras that disable the ability of the GTPases to dynamically be inactivated, leading to the constitutive and concurrent activation of a diverse array of signal pathways, for example, Raf/MEK/ERK and PI3K/Akt.[14] tissue studies have revealed the constitutive and concurrent activation of ERK and Akt in the progression of PCa, the majority of PCa tumors do not harbor RAS mutation (oncogenes).[15] Yet, it is generally acknowledged that the aberrant activation of Ras can shift PCa from androgen-dependent to independent,[16] whereas the expression of dominant-negative Ras attenuates androgen-independent phenotype,[17] indicating that Ras activation is responsible for the phenotype of PCa. In the current study of PCa, we investigated a pathway of metabolic and proto-oncogenic processes including Ras activation that aberrantly activates ERK and Akt. In the current study of PCa, we investigated a pathway of metabolic and proto-oncogenic processes including Ras activation that aberrantly activates ERK and Akt We denoted this as the mitochondrial-generated progression signal (mitoGPS) that transduces changes in mitochondrial genome in the early-stages of PCa into the advanced progression of the disease
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