Obesity promotes aerobic glycolysis in prostate cancer cells.

Obesity is the leading preventable comorbidity associated with increased prostate cancer-related recurrence and mortality. Epidemiological and clinical studies indicate that a body mass index >30 is associated with increased oxidative DNA damage within the prostate gland and increased prostate cancer-related mortality. Here we provide evidence that obesity promotes worse clinical outcome through induction of metabolic abnormalities known to promote genotoxic stress. We have previously reported that blood serum derived from obese mice may enhance the proliferative and invasive potential of human prostate cancer cell lines ex vivo. Here we show that a 1-h exposure of LNCaP or PacMetUT1 prostate cancer cell lines and nonmalignant RWPE-1 prostate epithelial cells to 2% serum from obese mice induces markers of aerobic glycolysis relative to those exposed to serum from nonobese mice. This metabolic change was correlated with accumulation of reactive oxygen species (ROS) and increased frequency of DNA double-strand breaks. Interestingly, N-tert-Butylhydroxylamine, an antioxidant, significantly suppressed markers of aerobic glycolysis in the cells exposed to the blood serum of obese mice, suggesting that ROS contributes to a metabolic shift toward aerobic glycolysis. Here we describe obesity-induced changes in key metabolic markers that impact prostate cancer cell progression and explore the role of antioxidants in ameliorating these effects.

A low dietary ratio of omega-6 to omega-3 Fatty acids may delay progression of prostate cancer.

Prostate cancer (PCa) is the second leading cause of cancer-related deaths in men. Studies show that consumption of polyunsaturated fatty acids (PUFA) modulates the development and progression of prostate cancer. High amounts of omega-6 fatty acids have been linked with increased prostate cancer risk, whereas omega-3 fatty acids have been shown to inhibit PCa growth. However, because omega-3 and omega-6 are both essential fatty acids and part of a complete diet, it is more relevant to determine the ideal ratio of the two that would allow patients to benefit from the therapeutic properties of omega-3 fatty acids. LNCaP prostate cancer cells were treated with dietary-based ratios of omega-6 to omega-3 fatty acids under hormone-deprivation conditions, and effects on various cellular processes were determined. A low omega-6 to omega-3 PUFA ratio can delay the progression of cells toward castration-resistance by suppressing pathways involved in prostate cancer progression, such as the Akt/mTOR/NFκB axis. It also suppresses the expression of cyclin D1, and activation of caspase-3 and annexin V staining shows induction of proapoptotic events. Taken together, our data demonstrates that maintaining a low omega-6 to omega-3 fatty acids ratio can enhance efficacy of hormone ablation therapy.

A Novel Class of Ribosome Modulating Agents Exploits Cancer Ribosome Heterogeneity to Selectively Target the CMS2 Subtype of Colorectal Cancer.

Ribosomes in cancer cells accumulate numerous patient-specific structural and functional modifications that facilitate tumor progression by modifying protein translation. We have taken a unique synthetic chemistry approach to generate novel macrolides, Ribosome modulating agents (RMA), that are proposed to act distal to catalytic sites and exploit cancer ribosome heterogeneity. The RMA ZKN-157 shows two levels of selectivity: (i) selective translation inhibition of a subset of proteins enriched for components of the ribosome and protein translation machinery that are upregulated by MYC; and (ii) selective inhibition of proliferation of a subset of colorectal cancer cell lines. Mechanistically, the selective ribosome targeting in sensitive cells triggered cell-cycle arrest and apoptosis. Consequently, in colorectal cancer, sensitivity to ZKN-157 in cell lines and patient-derived organoids was restricted to the consensus molecular subtype 2 (CMS2) subtype that is distinguished by high MYC and WNT pathway activity. ZKN-157 showed efficacy as single agent and, the potency and efficacy of ZKN-157 synergized with clinically approved DNA-intercalating agents which have previously been shown to inhibit ribogenesis as well. ZKN-157 thus represents a new class of ribosome modulators that display cancer selectivity through specific ribosome inhibition in the CMS2 subtype of colorectal cancer potentially targeting MYC-driven addiction to high protein translation. Significance: This study demonstrates that ribosome heterogeneity in cancer can be exploited to develop selective ribogenesis inhibitors. The colorectal cancer CMS2 subtype, with a high unmet need for therapeutics, shows vulnerability to our novel selective ribosome modulator. The mechanism suggests that other cancer subtypes with high MYC activation could also be targeted.