Altered metabolism in cancer: insights into energy pathways and therapeutic targets
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Cited by 4 publications
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Mendelian randomization study on the association of circulating ketone bodies with lung cancer and respiratory diseases
The liver produces various ketone bodies (KBs) including 3-Hydroxybutyrate (3-OHB), acetoacetate (AcAc), and acetone, with 3-OHB being the major component. Previous studies have shown that KBs protect against respiratory diseases; however, there is no evidence of a genetic link. To avoid biases existing in traditional observational studies, a two-sample Mendelian randomization (MR) analysis was carried out to investigate genetic causation and novel therapeutic uses for KBs. This study used databases from genome-wide association studies (GWAS) and single nucleotide polymorphisms as instrumental variables for KBs from a recently published metabonomics study ( n = 121,584) and respiratory diseases [lung cancer, n = 85,716; asthma, n = 127,669; chronic bronchitis, n = 450,422; chronic obstructive pulmonary disease (COPD), n = 468,475; FEV 1 /FVC < 0.7, n = 353,315] from their publicly available GWAS, respectively. Strong sets of instrumental variables ( P < 5 × 10 − 8 ) were selected, with inverse-variance weighted as the primary MR method. Sensitivity analyses included Cochran’s Q test, MR Egger, MR-PRESSO, leave-one-out test, and funnel plots. The Steiger test and reversed MR were used to exclude reverse causality. Additionally, independent replication MR studies were conducted using databases from another large public GWAS and similar methods as described above. After MR analyses and sensitivity filtering, we discovered a protective effect of 3-OHB on lung cancer (odds ratio [OR] = 0.771; 95% confidence interval [CI] = 0.648–0.916; P FDR =0.006), small cell carcinoma (OR = 0.485, 95% CI = 0.301–0.781, P FDR =0.006), asthma (OR = 0.585, 95% CI = 0.395–0.867, P FDR =0.010), chronic bronchitis (OR = 0.753, 95% CI = 0.570–0.994, P FDR =0.045), COPD (OR = 0.690, 95% CI = 0.535–0.890, P FDR =0.008) and lung function (OR = 0.970, 95%CI = 0.950–0.990, P FDR =0.008). In summary, our findings suggest that 3-OHB acts as a protective factor against lung cancer and respiratory diseases. However, heterogeneity implies that other mechanisms may also be involved in COPD improvement by 3-OHB. Supplementary Information The online version contains supplementary material available at 10.1038/s41598-024-81591-9.
Mendelian randomization study on the association of circulating ketone bodies with lung cancer and respiratory diseases
The liver produces various ketone bodies (KBs) including 3-Hydroxybutyrate (3-OHB), acetoacetate (AcAc), and acetone, with 3-OHB being the major component. Previous studies have shown that KBs protect against respiratory diseases; however, there is no evidence of a genetic link. To avoid biases existing in traditional observational studies, a two-sample Mendelian randomization (MR) analysis was carried out to investigate genetic causation and novel therapeutic uses for KBs. This study used databases from genome-wide association studies (GWAS) and single nucleotide polymorphisms as instrumental variables for KBs from a recently published metabonomics study ( n = 121,584) and respiratory diseases [lung cancer, n = 85,716; asthma, n = 127,669; chronic bronchitis, n = 450,422; chronic obstructive pulmonary disease (COPD), n = 468,475; FEV 1 /FVC < 0.7, n = 353,315] from their publicly available GWAS, respectively. Strong sets of instrumental variables ( P < 5 × 10 − 8 ) were selected, with inverse-variance weighted as the primary MR method. Sensitivity analyses included Cochran’s Q test, MR Egger, MR-PRESSO, leave-one-out test, and funnel plots. The Steiger test and reversed MR were used to exclude reverse causality. Additionally, independent replication MR studies were conducted using databases from another large public GWAS and similar methods as described above. After MR analyses and sensitivity filtering, we discovered a protective effect of 3-OHB on lung cancer (odds ratio [OR] = 0.771; 95% confidence interval [CI] = 0.648–0.916; P FDR =0.006), small cell carcinoma (OR = 0.485, 95% CI = 0.301–0.781, P FDR =0.006), asthma (OR = 0.585, 95% CI = 0.395–0.867, P FDR =0.010), chronic bronchitis (OR = 0.753, 95% CI = 0.570–0.994, P FDR =0.045), COPD (OR = 0.690, 95% CI = 0.535–0.890, P FDR =0.008) and lung function (OR = 0.970, 95%CI = 0.950–0.990, P FDR =0.008). In summary, our findings suggest that 3-OHB acts as a protective factor against lung cancer and respiratory diseases. However, heterogeneity implies that other mechanisms may also be involved in COPD improvement by 3-OHB. Supplementary Information The online version contains supplementary material available at 10.1038/s41598-024-81591-9.
Reprogramming SREBP1-dependent lipogenesis and inflammation in high-risk breast with licochalcone A: a novel path to cancer prevention
Several anti-estrogen drugs are proven to reduce breast cancer risk, but have had minimal acceptance and impact, due to their side effects. Additionally, these do not reduce the risk of estrogen receptor negative breast cancer. Candidate drugs that are under investigation for this purpose have unfavorable tolerability and safety profiles. Licochalcone A (LicA) from licorice is a prenylated chalcone which has antioxidant and anti-inflammatory effects, suppresses aromatase expression and activity, and reduces estrogen genotoxic metabolism in vivo. We evaluated its breast cancer preventive potential using microstructures obtained from mastectomy specimens of high-risk postmenopausal women. We treated these ex-vivo with LicA, followed by total RNA sequencing, differential gene expression and pathway analysis, followed by metabolic flux modeling. We observed profound downregulation of SREBF-dependent cholesterol biosynthesis, lipid metabolism, and PI3K-Akt pathways, along with significant upregulation of NRF2-dependent antioxidant and anti NF-kB-dependent inflammatory pathways. Additionally, NAD(P)H regenerating pentose phosphate shunt which supports these defense mechanisms was upregulated, in a direction unfavorable to nucleotide biosynthesis and proliferation. Drug matrix analysis of LicA-treated samples revealed significant transcriptomic similarities with statins. NanoString metabolism panel evaluations in microstructures from additional subjects confirmed these findings. Live cell imaging on 2 pre-malignant and 5 malignant breast cell lines treated with single and repeated doses of LicA showed antiproliferation, consistent with the downregulation of proliferative markers (SP1 and KLF4). Western blot analysis demonstrated suppression of SREBP1 in ER+ and ER- malignant breast cells and suppression of p-PI3K and p-AKT in cancer cells suggesting associations with antiproliferative efficacy of LicA. In vivo studies with subcutaneous LicA showed significant suppression of both luminal and triple negative xenografts in mice. Our data suggest that LicA reprograms metabolism and antioxidant responses, and is a promising candidate for further studies as a breast cancer risk reducing agent. Future studies with oral LicA in models of breast cancer prevention are warranted.
Emerging Role of Extracellular pH in Tumor Microenvironment as a Therapeutic Target for Cancer Immunotherapy
Identifying definitive biomarkers that predict clinical response and resistance to immunotherapy remains a critical challenge. One emerging factor is extracellular acidosis in the tumor microenvironment (TME), which significantly impairs immune cell function and contributes to immunotherapy failure. However, acidic conditions in the TME disrupt the interaction between cancer and immune cells, driving tumor-infiltrating T cells and NK cells into an inactivated, anergic state. Simultaneously, acidosis promotes the recruitment and activation of immunosuppressive cells, such as myeloid-derived suppressor cells and regulatory T cells (Tregs). Notably, tumor acidity enhances exosome release from Tregs, further amplifying immunosuppression. Tumor acidity thus acts as a “protective shield,” neutralizing anti-tumor immune responses and transforming immune cells into pro-tumor allies. Therefore, targeting lactate metabolism has emerged as a promising strategy to overcome this barrier, with approaches including buffer agents to neutralize acidic pH and inhibitors to block lactate production or transport, thereby restoring immune cell efficacy in the TME. Recent discoveries have identified genes involved in extracellular pH (pHe) regulation, presenting new therapeutic targets. Moreover, ongoing research aims to elucidate the molecular mechanisms driving extracellular acidification and to develop treatments that modulate pH levels to enhance immunotherapy outcomes. Additionally, future clinical studies are crucial to validate the safety and efficacy of pHe-targeted therapies in cancer patients. Thus, this review explores the regulation of pHe in the TME and its potential role in improving cancer immunotherapy.
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