Cytochrome c Deficiency Confers Apoptosome and Mitochondrial Dysfunction in African-American Men with Prostate Cancer

Abstract

Although African-American (AA) patients with prostate cancer tend to develop greater therapeutic resistance and faster prostate cancer recurrence compared with Caucasian-American (CA) men, the molecular mechanisms of this racial prostate cancer disparity remain undefined. In this study, we provide the first comprehensive evidence that cytochrome c deficiency in AA primary tumors and cancer cells abrogates apoptosome-mediated caspase activation and contributes to mitochondrial dysfunction, thereby promoting therapeutic resistance and prostate cancer aggressiveness in AA men. In AA prostate cancer cells, decreased nuclear accumulation of nuclear respiration factor 1 (Nrf1) and its subsequent loss of binding to the cytochrome c promoter mediated cytochrome c deficiency. The activation of cellular Myc (c-Myc) and NF-kB or inhibition of AKT prevented nuclear translocation of Nrf1. Genetic and pharmacologic inhibition of c-Myc and NF-kB or activation of AKT promoted Nrf1 binding to cytochrome c promoter, cytochrome c expression, caspase activation, and cell death. The lack of p-Drp1 S616 in AA prostate cancer cells contributed to defective cytochrome c release and increased resistance to apoptosis, indicating that restoration of cytochrome c alone may be insufficient to induce effective apoptosis. Cytochrome c deficiency promoted the acquisition of glycolytic phenotypes and mitochondrial dysfunction, whereas cytochrome c restoration via inhibition of c-Myc and NF-kB or activation of AKT attenuated glycolysis in AA prostate cancer cells. Inhibition of c-Myc and NF-kB enhanced the efficacy of docetaxel in tumor xenografts. Therefore, restoring cytochrome c may overcome therapeutic resistance and prostate cancer aggressiveness in AA men. Overall, this study provides the first comprehensive experimental, mechanistic, and clinical evidence for apoptosome and mitochondrial dysfunction in prostate cancer racial disparity. Significance: Mechanistic insights on prostate cancer health disparity among American men provide novel approaches to restore mitochondrial function, which can address therapeutic resistance and aggressiveness in African-American men with prostate cancer.

VDAC1 Conversely Correlates with Cytc Expression and Predicts Poor Prognosis in Human Breast Cancer Patients

“…Furthermore, Cytc was lower expressed in BC compared with benign breast lesions and low expression of Cytc was correlated with higher histological grade, ER status, PR status and recurrence. A similar correlation was found in prostate cancer which Cytc de ciency contributed to tumor invasiveness and faster recurrence [27]. Importantly, we also found that decreased expression of Cytc was an independent prognostic factor in breast cancer solid tumors and played a pivotal role in the poorer 5-DFS of that cohort of BC patients.…”

“…Jamsheed [26] et al demonstrated that in non-small cell lung cancer patients, Cytc level was lower than healthy individuals, and the lower expression of Cytc were associated with advanced stages, high grade histological differentiation and shorter overall survival. Rahul [27] et al explored that in prostate cancer, Cytc de ciency contributed to tumor invasiveness and therapeutic resistance, and leaded to faster recurrence. It has been widely reported that VDAC1 participates in the release of Cytc, which is able to signal Cytc to initiate the mitochondrial-mediated cell death cascade [28].…”

Optimization and Characterization of Protein Nanoparticles for the Targeted and Smart Delivery of Cytochrome c to Non-Small Cell Lung Carcinoma

“…Cell culture of Lewis Lung carcinoma for tumor implant: LLC cells (ATCC CRL-1642) were cultured in High-Glucose Dulbecco's Modified Eagle's Medium (DMEM) supplemented with 10% fetal bovine serum (FBS) and 1% Penicillin/Streptomycin/Amphotericin (PSA) to confluency, and these were gently scraped off the plate, pelleted, quantified. To induce a tumor, mice were subcutaneously injected 1x10 7 LLC cells in a 400µL total volume composed of 200µL ECM Growth factor reduced gel from Engelbreth-Holm-Swarm murine sarcoma (SIGMA), and 200µL cell suspension in media into the upper right dorsal area of their body.…”

“…Cytochrome c (Cyt c) release is one key event of the mitochondrial apoptotic pathway that triggers the caspase activation cascade [6]. It has been shown that deficiency of Cyt c can prevent appropriate apoptosome formation, inhibiting cell death and promoting cancer [7,8]. Several studies have shown that the direct external delivery of Cyt c to the cell cytosol can activate the caspase cascade and induce apoptosis in a dose-dependent manner [9,10].…”

Protein may be linked to racial disparities in prostate cancer

“…A new study published in Cancer Research suggests that certain cellular mechanisms may help to explain why African American men with prostate cancer tend to develop greater therapeutic resistance and faster disease recurrence than their white counterparts . Furthermore, according to investigators, the findings could create a pathway for new therapeutic targets.…”