ACSM1 and ACSM3 Regulate Fatty Acid Metabolism to Support Prostate Cancer Growth and Constrain Ferroptosis.

Solid tumors are highly reliant on lipids for energy, growth, and survival. In prostate cancer, the activity of the androgen receptor (AR) is associated with reprogramming of lipid metabolic processes. Here, we identified acyl-CoA synthetase medium chain family members 1 and 3 (ACSM1 and ACSM3) as AR-regulated mediators of prostate cancer metabolism and growth. ACSM1 and ACSM3 were upregulated in prostate tumors compared with nonmalignant tissues and other cancer types. Both enzymes enhanced proliferation and protected prostate cancer cells from death in vitro, whereas silencing ACSM3 led to reduced tumor growth in an orthotopic xenograft model. ACSM1 and ACSM3 were major regulators of the prostate cancer lipidome and enhanced energy production via fatty acid oxidation. Metabolic dysregulation caused by loss of ACSM1/3 led to mitochondrial oxidative stress, lipid peroxidation, and cell death by ferroptosis. Conversely, elevated ACSM1/3 activity enabled prostate cancer cells to survive toxic levels of medium chain fatty acids and promoted resistance to ferroptosis-inducing drugs and AR antagonists. Collectively, this study reveals a tumor-promoting function of medium chain acyl-CoA synthetases and positions ACSM1 and ACSM3 as key players in prostate cancer progression and therapy resistance. Significance: Androgen receptor-induced ACSM1 and ACSM3 mediate a metabolic pathway in prostate cancer that enables the utilization of medium chain fatty acids for energy production, blocks ferroptosis, and drives resistance to clinically approved antiandrogens.

Targeting hyaluronan-mediated motility receptor (HMMR) enhances response to androgen receptor signalling inhibitors in prostate cancer.

BACKGROUND: Resistance to androgen receptor signalling inhibitors (ARSIs) represents a major clinical challenge in prostate cancer. We previously demonstrated that the ARSI enzalutamide inhibits only a subset of all AR-regulated genes, and hypothesise that the unaffected gene networks represent potential targets for therapeutic intervention. This study identified the hyaluronan-mediated motility receptor (HMMR) as a survival factor in prostate cancer and investigated its potential as a co-target for overcoming resistance to ARSIs. METHODS: RNA-seq, RT-qPCR and Western Blot were used to evaluate the regulation of HMMR by AR and ARSIs. HMMR inhibition was achieved via siRNA knockdown or pharmacological inhibition using 4-methylumbelliferone (4-MU) in prostate cancer cell lines, a mouse xenograft model and patient-derived explants (PDEs). RESULTS: HMMR was an AR-regulated factor that was unaffected by ARSIs. Genetic (siRNA) or pharmacological (4-MU) inhibition of HMMR significantly suppressed growth and induced apoptosis in hormone-sensitive and enzalutamide-resistant models of prostate cancer. Mechanistically, 4-MU inhibited AR nuclear translocation, AR protein expression and subsequent downstream AR signalling. 4-MU enhanced the growth-suppressive effects of 3 different ARSIs in vitro and, in combination with enzalutamide, restricted proliferation of prostate cancer cells in vivo and in PDEs. CONCLUSION: Co-targeting HMMR and AR represents an effective strategy for improving response to ARSIs.

Biochar as a negative emission technology: A synthesis of field research on greenhouse gas emissions.

Biochar is one of the few nature-based technologies with potential to help achieve net-zero emissions agriculture. Such an outcome would involve the mitigation of greenhouse gas (GHG) emission from agroecosystems and optimization of soil organic carbon sequestration. Interest in biochar application is heightened by its several co-benefits. Several reviews summarized past investigations on biochar, but these reviews mostly included laboratory, greenhouse, and mesocosm experiments. A synthesis of field studies is lacking, especially from a climate change mitigation standpoint. Our objectives are to (1) synthesize advances in field-based studies that have examined the GHG mitigation capacity of soil application of biochar and (2) identify limitations of the technology and research priorities. Field studies, published before 2022, were reviewed. Biochar has variable effects on GHG emissions, ranging from decrease, increase, to no change. Across studies, biochar reduced emissions of nitrous oxide (N2 O) by 18% and methane (CH4 ) by 3% but increased carbon dioxide (CO2 ) by 1.9%. When biochar was combined with N-fertilizer, it reduced CO2 , CH4 , and N2 O emissions in 61%, 64%, and 84% of the observations, and biochar plus other amendments reduced emissions in 78%, 92%, and 85% of the observations, respectively. Biochar has shown potential to reduce GHG emissions from soils, but long-term studies are needed to address discrepancies in emissions and identify best practices (rate, depth, and frequency) of biochar application to agricultural soils.

A feedback loop between the androgen receptor and 6-phosphogluoconate dehydrogenase (6PGD) drives prostate cancer growth.

Alterations to the androgen receptor (AR) signalling axis and cellular metabolism are hallmarks of prostate cancer. This study provides insight into both hallmarks by uncovering a novel link between AR and the pentose phosphate pathway (PPP). Specifically, we identify 6-phosphogluoconate dehydrogenase (6PGD) as an androgen-regulated gene that is upregulated in prostate cancer. AR increased the expression of 6PGD indirectly via activation of sterol regulatory element binding protein 1 (SREBP1). Accordingly, loss of 6PGD, AR or SREBP1 resulted in suppression of PPP activity as revealed by 1,2-13C2 glucose metabolic flux analysis. Knockdown of 6PGD also impaired growth and elicited death of prostate cancer cells, at least in part due to increased oxidative stress. We investigated the therapeutic potential of targeting 6PGD using two specific inhibitors, physcion and S3, and observed substantial anti-cancer activity in multiple models of prostate cancer, including aggressive, therapy-resistant models of castration-resistant disease as well as prospectively collected patient-derived tumour explants. Targeting of 6PGD was associated with two important tumour-suppressive mechanisms: first, increased activity of the AMP-activated protein kinase (AMPK), which repressed anabolic growth-promoting pathways regulated by acetyl-CoA carboxylase 1 (ACC1) and mammalian target of rapamycin complex 1 (mTORC1); and second, enhanced AR ubiquitylation, associated with a reduction in AR protein levels and activity. Supporting the biological relevance of positive feedback between AR and 6PGD, pharmacological co-targeting of both factors was more effective in suppressing the growth of prostate cancer cells than single-agent therapies. Collectively, this work provides new insight into the dysregulated metabolism of prostate cancer and provides impetus for further investigation of co-targeting AR and the PPP as a novel therapeutic strategy.

Human DECR1 is an androgen-repressed survival factor that regulates PUFA oxidation to protect prostate tumor cells from ferroptosis.

Fatty acid ß-oxidation (FAO) is the main bioenergetic pathway in human prostate cancer (PCa) and a promising novel therapeutic vulnerability. Here we demonstrate therapeutic efficacy of targeting FAO in clinical prostate tumors cultured ex vivo, and identify DECR1, encoding the rate-limiting enzyme for oxidation of polyunsaturated fatty acids (PUFAs), as robustly overexpressed in PCa tissues and associated with shorter relapse-free survival. DECR1 is a negatively-regulated androgen receptor (AR) target gene and, therefore, may promote PCa cell survival and resistance to AR targeting therapeutics. DECR1 knockdown selectively inhibited ß-oxidation of PUFAs, inhibited proliferation and migration of PCa cells, including treatment resistant lines, and suppressed tumor cell proliferation and metastasis in mouse xenograft models. Mechanistically, targeting of DECR1 caused cellular accumulation of PUFAs, enhanced mitochondrial oxidative stress and lipid peroxidation, and induced ferroptosis. These findings implicate PUFA oxidation via DECR1 as an unexplored facet of FAO that promotes survival of PCa cells.

Nitrous Oxide Fluxes in Fertilized L. Plantations across a Gradient of Soil Drainage Classes.

The effect of fertilizer management on nitrous oxide (NO) fluxes in agricultural ecosystems is well documented; however, our knowledge of these effects in managed forests is minimal. We established a comprehensive research study to address this knowledge gap across a range of soil drainage classes (poorly, moderately, and well drained) common in southern pine plantation management. Fertilizer treatments in each drainage class comprised of control (no fertilizer), urea + phosphorus (P), and P-coated urea fertilizer (CUF). Fertilization (168 kg N ha) occurred independently during the spring, summer, and fall to assess the effects of application timing. Nitrous oxide sampling, using vented static chambers, started immediately after seasonal fertilizer application and was performed every 6 wk for more than 1 yr. Time-integrated net annual NO emissions increased with urea (1.15 kg NO-N ha) and CUF (0.88 kg NO-N ha) application compared with unfertilized control (0.22 kg NO-N ha). Mean annual NO flux was significantly increased with fall fertilization (1.17 kg NO-N ha) relative to spring (0.73 kg NO-N ha) or summer (0.33 kg NO-N ha). Similarly, average annual NO flux was higher in poorly drained soils (1.40 kg NO-N ha) than in moderately drained (0.46 kg NO-N ha) and well-drained soils (0.39 kg NO-N ha). This study suggests that NO emissions after fertilization can be minimized by avoiding fall fertilization and poorly drained soils and by selecting enhanced-efficiency N fertilizers over urea.

Greenhouse gas emissions and global warming potential of reclaimed forest and grassland soils.

Although greenhouse gas (GHG) emissions from soils are important, reclaimed mine soil (RMS) ecosystems are not widely assessed. Postreclamation land uses (forest, hay, and pasture) were investigated to: (i) monitor the magnitude of GHG fluxes, (ii) estimate their global warming potential (GWP), (iii) identify the relationship between GHG fluxes and soil properties, and (iv) develop a soil quality index by principal component analysis (PCA). The GHG fluxes were measured for 1 yr cycle and simultaneous measurements were also made for soil moisture and temperature. The RMS-forest, -hay, and -pasture land uses had weighted average fluxes of 1.16, 1.66, and 3.06 g CO(2)-C m(-2) d(-1); 0.33, 0.48 and 1.1 mg CH(4)-C m(-2) d(-1); and 0.33, 0.70, and 1.06 mg N(2)O-N m(-2) d(-1), respectively. The CO(2), CH(4), and N(2)O fluxes were consistently high in the RMS-pasture and low in the RMS-forest. The GWP (CO(2)-C equivalent) of the postreclamation land uses was in the order of RMS-forest (4.5 Mg ha(-1) yr(-1)) = RMS-hay (6.8 Mg ha(-1) yr(-1)) < RMS-pasture (12.3 Mg ha(-1) yr(-1)). The PCA showed that four PCs with eigenvalues > 1 explained 88.8% of the total variance in the soil properties. The first PC is mostly characterized by soil physical properties and the second by chemical properties. Soil and air temperatures were positively correlated with CO(2), CH(4), and N(2)O fluxes. The results suggest that GWP from RMS can be minimized by establishing forest land use.

Soil carbon and nitrogen in 28-year-old land uses in reclaimed coal mine soils of Ohio.

Carbon (C) and nitrogen (N) play an important role in the restoration of ecosystem functions of reclaimed mine soils (RMSs). Postreclamation land use in RMSs affects soil C and N pools and fluxes. We compared the effects of 28-yr-old postreclamation land uses (forest, hay, and pasture) on selected chemical properties of soil, and C and N pools in reference to undisturbed forest and moderately disturbed agricultural land use in southeastern Ohio. The electrical conductivity was higher in RMSs under hay than that in pasture and forest land uses. The RMSs under pasture, hay, and forest had moderately acidic, neutral to slightly alkaline, and slightly alkaline pH, respectively. In the 0- to 5-cm soil depth, soil organic C (SOC) was higher in RMSs under pasture by 99% and under hay by 52% over that under forest. Similarly, total nitrogen (TN) was higher in RMSs under pasture by 98% and under hay by 43% over that under forest. Aggregate-associated SOC concentration in the 0- to 5-cm depth decreased in the order of RMSs under hay > RMSs under pasture > RMSs under forest. The SOC pools in the 0- to 30-cm depth decreased in the order of RMSs under hay = RMSs under pasture > RMSs under forest = undisturbed forest = agriculture land use. Nitrogen pools followed a similar trend. Hay land use has a better potential for improving soil quality in RMSs by enhancing chemical properties and SOC and TN pools than forest or pasture land uses.

Ecosystem carbon budgeting and soil carbon sequestration in reclaimed mine soil.

Global warming risks from emissions of green house gases (GHGs) by anthropogenic activities, and possible mitigation strategies of terrestrial carbon (C) sequestration have increased the need for the identification of ecosystems with high C sink capacity. Depleted soil organic C (SOC) pools of reclaimed mine soil (RMS) ecosystems can be restored through conversion to an appropriate land use and adoption of recommended management practices (RMPs). The objectives of this paper are to (1) synthesize available information on carbon dioxide (CO2) emissions from coal mining and combustion activities, (2) understand mechanisms of SOC sequestration and its protection, (3) identify factors affecting C sequestration potential in RMSs, (4) review available methods for the estimation of ecosystem C budget (ECB), and (5) identify knowledge gaps to enhance C sink capacity of RMS ecosystems and prioritize research issues. The drastic perturbations of soil by mining activities can accentuate CO2 emission through mineralization, erosion, leaching, changes in soil moisture and temperature regimes, and reduction in biomass returned to the soil. The reclamation of drastically disturbed soils leads to improvement in soil quality and development of soil pedogenic processes accruing the benefit of SOC sequestration and additional income from trading SOC credits. The SOC sequestration potential in RMS depends on amount of biomass production and return to soil, and mechanisms of C protection. The rate of SOC sequestration ranges from 0.1 to 3.1 Mg ha(-1) yr(-1) and 0.7 to 4 Mg ha(-1) yr(-1) in grass and forest RMS ecosystem, respectively. Proper land restoration alone could off-set 16 Tg CO2 in the U.S. annually. However, the factors affecting C sequestration and protection in RMS leading to increase in microbial activity, nutrient availability, soil aggregation, C build up, and soil profile development must be better understood in order to formulate guidelines for development of an holistic approach to sustainable management of these ecosystems. The ECBs of RMS ecosystems are not well understood. An ecosystem method of evaluating ECB of RMS ecosystems is proposed.