Metabolic alterations are a key hallmark of cancer cells, and the augmented synthesis and use of nucleotide triphosphates is a critical and universal metabolic dependency of cancer cells across ...different cancer types and genetic backgrounds. Many of the aggressive behaviours of cancer cells, including uncontrolled proliferation, chemotherapy resistance, immune evasion and metastasis, rely heavily on augmented nucleotide metabolism. Furthermore, most of the known oncogenic drivers upregulate nucleotide biosynthetic capacity, suggesting that this phenotype is a prerequisite for cancer initiation and progression. Despite the wealth of data demonstrating the efficacy of nucleotide synthesis inhibitors in preclinical cancer models and the well-established clinical use of these drugs in certain cancer settings, the full potential of these agents remains unrealized. In this Review, we discuss recent studies that have generated mechanistic insights into the diverse biological roles of hyperactive cancer cell nucleotide metabolism. We explore opportunities for combination therapies that are highlighted by these recent advances and detail key questions that remain to be answered, with the goal of informing urgently warranted future studies.
Biohydrogen production from waste materials has been recognized as the promising step towards bioremediation and green energy generation. A large number of microorganisms and diverse range of waste ...materials have been widely studied for H2 production. However, H2 production efficiencies vary depending upon the type of organism, type and composition of waste, physiological conditions, and the reactor used. Some research groups suggest integrated dark- and photo-fermentation processes for optimum utilization of the substrate and higher H2 yield per mol of substrate. Integration of these two processes increases the H2 yield, and seems suitable for commercial H2 production. Review and evaluation of the published data suggest that integrated system holds greater promise for commercial H2 production. The present review deals with the possibilities of enhancing H2 yield by integrating dark- and photo-fermentation for commercial use.
•H2 production by dark- and photo-fermentation.•Integrated system holds promise for commercial H2 production.•Integrated system utilized substrate effectively and increased H2 yield.
Cholesterol is a multifaceted metabolite that is known to modulate processes in cancer, atherosclerosis, and autoimmunity. A common denominator between these diseases appears to be the immune system, ...in which many cholesterol-associated metabolites impact both adaptive and innate immunity. Many cancers display altered cholesterol metabolism, and recent studies demonstrate that manipulating systemic cholesterol metabolism may be useful in improving immunotherapy responses. However, cholesterol can have both proinflammatory and anti-inflammatory roles in mammals, acting via multiple immune cell types, and depending on context. Gaining mechanistic insights into various cholesterol-related metabolites can improve our understanding of their functions and extensive effects on the immune system, and ideally will inform the design of future therapeutic strategies against cancer and/or other pathologies.
Frequent alterations in cholesterol homeostasis have classically been thought to support the production of building blocks for growth. However, the immunomodulatory properties of cholesterol, oxysterols, statins, and related metabolites can significantly impact on the mammalian immune system.Targeting cholesterol imbalances might be exploited to hinder tumor growth and restore immune functions in particular malignancies.Excessive cholesterol can lead to CD8+ T cell exhaustion in some models. Recent evidence suggests that targeting the cholesterol pathway could be a therapeutic approach that might synergize with PD-1 checkpoint blockade immunotherapy in some cancers.Immune cells require cholesterol for activation. Therefore, excessive targeting or depletion of cholesterol and subsequent putative effects on immune cells should be major considerations.Targeting the cholesterol pathway might be a promising approach in anticancer therapies. However, careful consideration must be given to the tumor microenvironment and the locations and contexts in which the pathway can be targeted.
Pancreatic ductal adenocarcinoma (PDAC) is characterized by KRAS- and autophagy-dependent tumorigenic growth, but the role of KRAS in supporting autophagy has not been established. We show that, to ...our surprise, suppression of KRAS increased autophagic flux, as did pharmacological inhibition of its effector ERK MAPK. Furthermore, we demonstrate that either KRAS suppression or ERK inhibition decreased both glycolytic and mitochondrial functions. We speculated that ERK inhibition might thus enhance PDAC dependence on autophagy, in part by impairing other KRAS- or ERK-driven metabolic processes. Accordingly, we found that the autophagy inhibitor chloroquine and genetic or pharmacologic inhibition of specific autophagy regulators synergistically enhanced the ability of ERK inhibitors to mediate antitumor activity in KRAS-driven PDAC. We conclude that combinations of pharmacologic inhibitors that concurrently block both ERK MAPK and autophagic processes that are upregulated in response to ERK inhibition may be effective treatments for PDAC.
Metastasis is a key contributor to mortality in patients with cancer. While many regulators of metastasis have been identified, critical targets to prevent and inhibit metastatic tumor growth remain ...elusive. A recent study in this issue of Cancer Research by Deng and colleagues compared gene expression signatures between primary esophageal squamous cell carcinoma tumors and metastatic tumors and combined the analysis with genes induced in metastatic cancer cell lines, which identified anoctamin 1 (ANO1) as a key driver of metastasis. ANO1 caused cholesterol accumulation by inhibiting LXR signaling and decreased cholesterol hydroxylation by downregulating the expression of cholesterol hydroxylase CYP27A1. ANO1 also regulated tumor cell-fibroblast cross-talk that contributed to inflammatory cytokine signaling (IL1β) and metastasis. Through in silico analysis, the study identified a novel small-molecule inhibitor of ANO1 that decreased tumor burden at a metastatic site. These studies provide novel insights into the role of ANO1 in cellular cholesterol metabolism and associated signaling in mediating metastasis. See related article by Deng et al., p. 1851.
Fascin is a pro‐metastasis actin‐bundling protein overexpressed in all carcinomas. This review will cover the biochemical basis for fascin‐bundling activity, the mechanisms by which cancer cells ...upregulate fascin expression and the mechanism underlying fascin‐mediated cancer cell migration, invasion, and metastatic colonization. We propose that fascin has broad roles in both metastatic dissemination and metastatic colonization. Understanding these mechanisms will be crucial to the development of anti‐metastasis therapeutics targeting fascin.
Fascin is an F‐actin‐bundling protein that cross‐links individual actin filaments into straight and stiff bundles. Fascin overexpression in cancer is strongly associated with poor prognosis and metastatic progression across different cancer types. It is well established that fascin plays a causative role in promoting metastatic progression. We will review the recent progress in our understanding of mechanisms underlying fascin‐mediated cancer metastasis. This review will cover the biochemical basis for fascin‐bundling activity, the mechanisms by which cancer cells upregulate fascin expression and the mechanism underlying fascin‐mediated cancer cell migration, invasion, and metastatic colonization. We propose that fascin has broad roles in both metastatic dissemination and metastatic colonization. Understanding these mechanisms will be crucial to the development of anti‐metastasis therapeutics targeting fascin.
The mechanistic understanding of nascent RNAs in transcriptional control remains limited. Here, by a high sensitivity method methylation-inscribed nascent transcripts sequencing (MINT-seq), we ...characterized the landscapes of N6-methyladenosine (m6A) on nascent RNAs. We uncover heavy but selective m6A deposition on nascent RNAs produced by transcription regulatory elements, including promoter upstream antisense RNAs and enhancer RNAs (eRNAs), which positively correlates with their length, inclusion of m6A motif, and RNA abundances. m6A-eRNAs mark highly active enhancers, where they recruit nuclear m6A reader YTHDC1 to phase separate into liquid-like condensates, in a manner dependent on its C terminus intrinsically disordered region and arginine residues. The m6A-eRNA/YTHDC1 condensate co-mixes with and facilitates the formation of BRD4 coactivator condensate. Consequently, YTHDC1 depletion diminished BRD4 condensate and its recruitment to enhancers, resulting in inhibited enhancer and gene activation. We propose that chemical modifications of eRNAs together with reader proteins play broad roles in enhancer activation and gene transcriptional control.
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•MINT-seq is of high sensitivity to characterize m6A methylome on nascent RNAs•There is a pervasive but also selective m6A deposition to long and stable eRNAs•m6A-eRNAs recruit YTHDC1 to enhancers to stimulate enhancer and gene activation•m6A-eRNA/YTHDC1 phase separate to facilitate transcriptional condensate formation
Lee, Wang, Xiong, et al. characterized nascent RNA m6A methylome in human cells, finding a pervasive existence of m6A-marked eRNAs. These m6A-modified eRNAs recruit the nuclear m6A reader YTHDC1 to partition into liquid-like condensates, which facilitate formation of transcriptional activator condensates and therefore gene activation.
PARP-1, a nuclear protein, is one of the key member of the DNA repair assembly and thereby emerged as an attractive target in anti-cancer drug discovery. PARP-1 plays a key role in terms of base ...excision repair, which is an important pathway for cell survival in breast cancer with BRCA1/BRCA2-mutation. In this scenario, the goal of this study was to identify novel prototypes of PARP-1 inhibitors for the development of antitumor therapeutics to treat breast cancer. Thus, a structure-based drug design exploration was first conducted using an in-house library, focusing on triazole-thione and alkylsulfanyl-triazole scaffold. Hits with good binding affinity and better predicted inhibitory potential were also tested for their PARP-1 inhibitory activity. Moreover, the selected compounds were evaluated for their cytotoxicity in-vitro. This approach led to the identification of few novel compounds showing interesting anti-proliferative potential in low micromolar range. Results disclosed that the identified lead molecules were efficiently impeding cell migration and cell proliferation, potentially by interfering with PARP-1 enzymatic activities.
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•SBDD allowed the identification of 1,2,4-triazoles as new scaffold for PARP-1 inhibitors.•In-vitro enzymatic assay against PARP-1 validated the potency of the selected hits.•Some compounds possesses anti-proliferative activity in MCF-7 breast cancer cell line.•The compounds significantly influence cytotoxicity behaviour by apoptosis activation.
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