Prostate cancer (PCa) affects millions of men worldwide and is a major cause of cancer-related mortality. Race-associated PCa health disparities are also common and are of both social and clinical concern. Most PCa is diagnosed early due to PSA-based screening, but it fails to discern between indolent and aggressive PCa. Androgen or androgen receptor-targeted therapies are standard care of treatment for locally advanced and metastatic disease, but therapy resistance is common. Mitochondria, the powerhouse of cells, are unique subcellular organelles that have their own genome. A large majority of mitochondrial proteins are, however, nuclear-encoded and imported after cytoplasmic translation. Mitochondrial alterations are common in cancer, including PCa, leading to their altered functions. Aberrant mitochondrial function affects nuclear gene expression in retrograde signaling and promotes tumor-supportive stromal remodeling. In this article, we discuss mitochondrial alterations that have been reported in PCa and review the literature related to their roles in PCa pathobiology, therapy resistance, and racial disparities. We also discuss the translational potential of mitochondrial alterations as prognostic biomarkers and as effective targets for PCa therapy.
Breast cancer (BC) is the most common non-cutaneous malignancy and the second leading cause of cancer-related death in American women. Health disparities in incidence and clinical outcome are also reported among different racial groups, most notably African American (AA) women, who are often diagnosed at a young age with aggressive BC and exhibit greater mortality than Caucasian American (CA) women. Since socioeconomic difficulties can have tremendous impact on psychophysiology besides limiting the access to optimal healthcare, we examined the serum levels of stress (cortisol) and satiety (leptin) hormones as well as inflammatory cytokines (resistin and interleukin-6/IL-6) in AA and CA women. To observe a potential epigenomic connection, we also performed profiling of a targeted set of exosomal microRNAs in serum samples. The study was conducted under an Institutional Review Board (IRB) approved protocol. All subjects participated voluntarily, and their consents were obtained. Serum levels of resistin, IL-6, leptin, and cortisol were quantified by Enzyme linked Immunosorbent Assay (ELISA) using commercial kits. Exosomes were isolated using precipitation method and recovered by standard centrifugation. Total RNA was isolated from exosomal preps and subjected to stem-loop RT-PCR for quantitation of a set of inflammation-associated microRNAs. We found that the levels of resistin, leptin, IL-6 and cortisol were higher in women with a BC diagnosis than non-BC subjects. Moreover, AA women with or without BC showed significantly higher levels of these cytokines and hormones in their serum as compared to the CA women with or without a BC diagnosis, respectively. We also observed differential expression of several microRNAs in serum of BC women as compared to their normal counterparts, of which five (miR511, miR33a, miR27a, miR6794, miR143-3p) exhibited highest presence in serum exosomes of AA women with BC. Together, these findings suggest that relatively greater exposure of minority women to social stressors may have epigenomic consequences and may potentially be linked to the observed BC racial health disparities. Citation Format: Sarabjeet Kour Sudan, Kunwar Somesh Vikramdeo, Amod Sharma, Sachin Kumar Deshmukh, Sanjeev Kumar Srivastava, Teja Poosarla, Nicolette P. Holliday, Donna L. Dyess, Ajay P. Singh, Seema Singh. Racially disparate serum levels of inflammatory cytokines, satiety and stress hormones, and exosomal microRNAs in women with or without a breast cancer diagnosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2212.
Cortisol, the primary stress hormone, can contribute to cancer development through a variety of mechanisms. In a population-based research study, we have detected high serum levels of cortisol and several exosomal microRNAs (miRs) in women with a breast cancer (BC) diagnosis than non-cancer female subjects. In this study, we identified a positive correlation of cortisol levels with an exosomal miRNA, miR-143-3p, in serum samples. Furthermore, we observed an upregulation of miR-143-3p in human monocyte (THP1 and U937)-derived macrophages upon treatment with cortisol but not in BC cell lines (MDA-MB-468 and MDA-MB-231). Enhanced levels of miR-143-3p were also found in exosomes collected from the cortisol-treated macrophages. Expression of miR-145 (transcribed as cluster miRNA with miR-143-3p) was also upregulated in cortisol-treated macrophages but their enhanced levels were not detected in shed exosomes. In silico analysis identified glucocorticoid-response elements (GREs) in the upstream promoter sequence, which exhibited elicited transcriptional activity in response to cortisol in a luciferase-based promoter-reporter assay. Direct binding of glucocorticoid receptor (GR) to the regulatory sequence containing region was confirmed by chromatin immunoprecipitation. We further observed that cortisol treatment inhibited IFN-γ-induced M1 polarization, while caused alternative M2 polarization of macrophages and these effects were inhibited by pre-treatment with miR-143-3p and miR-145 inhibitors. Cortisol treatment reduced ECAR/OCR ratio in macrophages suggesting reduced glycolysis and/or increased oxidative phosphorylation. This effect was neutralized by functional inhibition of miR-143-3p and miR-145. Computational analysis using web-based servers (TargetScan and miRDB) identified HK2 (hexokinase-2) and ADPGK (ADP-dependent glucokinase) as potential targets of miR-143-3p and mir-145, respectively, whose expression was downregulated in cortisol-treated macrophages and rescued upon miR-143-3p and miR-145 inhibition. Direct targeting of 3′- untranslated regions of HK2 and ADPGK by miR-143-3p and miR-145, respectively, was confirmed in luciferase-based reporter assays. Altogether, we have identified novel cortisol-regulated miRNAs that inhibit classical M1 polarization and induce alternative M2 polarization by reprogramming of glucose metabolism. Our findings have relevance in establishing an indirect connection of chronic stress with cancer development via immunosuppressive effect of cortisol, and could be helpful in risk prediction and management efforts. Citation Format: Amod Sharma, Kunwar Somesh Vikramdeo, Sarabjeet Kour Sudan, Sachin Kumar Deshmukh, Ajay P. Singh, Seema Singh. Cortisol induces the expression of miR-143-3p/miR-145 cluster in macrophages to affect macrophage polarization via reprogramming of glucose metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1546.
A tumor is not just comprised of cancer cells but also a heterogeneous group of infiltrating and resident host cells, as well as their secreted factors that form the extracellular matrix [...]
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