RESUMEN
Mercury (Hg) researchers have made progress in understanding atmospheric Hg, especially with respect to oxidized Hg (HgII) that can represent 2 to 20% of Hg in the atmosphere. Knowledge developed over the past â¼10 years has pointed to existing challenges with current methods for measuring atmospheric Hg concentrations and the chemical composition of HgII compounds. Because of these challenges, atmospheric Hg experts met to discuss limitations of current methods and paths to overcome them considering ongoing research. Major conclusions included that current methods to measure gaseous oxidized and particulate-bound Hg have limitations, and new methods need to be developed to make these measurements more accurate. Developing analytical methods for measurement of HgII chemistry is challenging. While the ultimate goal is the development of ultrasensitive methods for online detection of HgII directly from ambient air, in the meantime, new surfaces are needed on which HgII can be quantitatively collected and from which it can be reversibly desorbed to determine HgII chemistry. Discussion and identification of current limitations, described here, provide a basis for paths forward. Since the atmosphere is the means by which Hg is globally distributed, accurately calibrated measurements are critical to understanding the Hg biogeochemical cycle.
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Contaminantes Atmosféricos , Atmósfera , Monitoreo del Ambiente , Mercurio , Mercurio/análisis , Atmósfera/química , Monitoreo del Ambiente/métodos , Contaminantes Atmosféricos/análisisRESUMEN
The ribotoxic stress response (RSR) is a signaling pathway in which the p38- and c-Jun N-terminal kinase (JNK)-activating mitogen-activated protein kinase kinase kinase (MAP3K) ZAKα senses stalling and/or collision of ribosomes. Here, we show that reactive oxygen species (ROS)-generating agents trigger ribosomal impairment and ZAKα activation. Conversely, zebrafish larvae deficient for ZAKα are protected from ROS-induced pathology. Livers of mice fed a ROS-generating diet exhibit ZAKα-activating changes in ribosomal elongation dynamics. Highlighting a role for the RSR in metabolic regulation, ZAK-knockout mice are protected from developing high-fat high-sugar (HFHS) diet-induced blood glucose intolerance and liver steatosis. Finally, ZAK ablation slows animals from developing the hallmarks of metabolic aging. Our work highlights ROS-induced ribosomal impairment as a physiological activation signal for ZAKα that underlies metabolic adaptation in obesity and aging.
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Envejecimiento , MAP Quinasa Quinasa Quinasa 3 , Obesidad , Especies Reactivas de Oxígeno , Ribosomas , Estrés Fisiológico , Animales , Ratones , Envejecimiento/metabolismo , MAP Quinasa Quinasa Quinasa 3/genética , MAP Quinasa Quinasa Quinasa 3/metabolismo , Obesidad/metabolismo , Biosíntesis de Proteínas , Especies Reactivas de Oxígeno/metabolismo , Ribosomas/metabolismo , Pez Cebra , Ratones NoqueadosRESUMEN
The genomic landscape of colorectal cancer (CRC) is shaped by inactivating mutations in tumour suppressors such as APC, and oncogenic mutations such as mutant KRAS. Here we used genetically engineered mouse models, and multimodal mass spectrometry-based metabolomics to study the impact of common genetic drivers of CRC on the metabolic landscape of the intestine. We show that untargeted metabolic profiling can be applied to stratify intestinal tissues according to underlying genetic alterations, and use mass spectrometry imaging to identify tumour, stromal and normal adjacent tissues. By identifying ions that drive variation between normal and transformed tissues, we found dysregulation of the methionine cycle to be a hallmark of APC-deficient CRC. Loss of Apc in the mouse intestine was found to be sufficient to drive expression of one of its enzymes, adenosylhomocysteinase (AHCY), which was also found to be transcriptionally upregulated in human CRC. Targeting of AHCY function impaired growth of APC-deficient organoids in vitro, and prevented the characteristic hyperproliferative/crypt progenitor phenotype driven by acute deletion of Apc in vivo, even in the context of mutant Kras. Finally, pharmacological inhibition of AHCY reduced intestinal tumour burden in ApcMin/+ mice indicating its potential as a metabolic drug target in CRC.
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Neoplasias Colorrectales , Animales , Humanos , Ratones , Adenosilhomocisteinasa/genética , Adenosilhomocisteinasa/metabolismo , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Metabolómica , Mutación , Proteínas Proto-Oncogénicas p21(ras)/genéticaRESUMEN
Translational regulation impacts both pluripotency maintenance and cell differentiation. To what degree the ribosome exerts control over this process remains unanswered. Accumulating evidence has demonstrated heterogeneity in ribosome composition in various organisms. 2'-O-methylation (2'-O-me) of rRNA represents an important source of heterogeneity, where site-specific alteration of methylation levels can modulate translation. Here, we examine changes in rRNA 2'-O-me during mouse brain development and tri-lineage differentiation of human embryonic stem cells (hESCs). We find distinct alterations between brain regions, as well as clear dynamics during cortex development and germ layer differentiation. We identify a methylation site impacting neuronal differentiation. Modulation of its methylation levels affects ribosome association of the fragile X mental retardation protein (FMRP) and is accompanied by an altered translation of WNT pathway-related mRNAs. Together, these data identify ribosome heterogeneity through rRNA 2'-O-me during early development and differentiation and suggest a direct role for ribosomes in regulating translation during cell fate acquisition.
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ARN Ribosómico , Ribosomas , Humanos , Animales , Ratones , Metilación , Ribosomas/metabolismo , ARN Ribosómico/genética , ARN Ribosómico/metabolismo , Diferenciación Celular , Neurogénesis/genética , Proteínas Ribosómicas/metabolismoRESUMEN
Intraepithelial lymphocytes (IEL) expressing γδ T-cell receptors (γδTCR) play key roles in elimination of colon cancer. However, the precise mechanisms by which progressing cancer cells evade immunosurveillance by these innate T cells are unknown. Here, we investigated how loss of the Apc tumor suppressor in gut tissue could enable nascent cancer cells to escape immunosurveillance by cytotoxic γδIELs. In contrast with healthy intestinal or colonic tissue, we found that γδIELs were largely absent from the microenvironment of both mouse and human tumors, and that butyrophilin-like (BTNL) molecules, which can critically regulate γδIEL through direct γδTCR interactions, were also downregulated in tumors. We then demonstrated that ß-catenin activation through loss of Apc rapidly suppressed expression of the mRNA encoding the HNF4A and HNF4G transcription factors, preventing their binding to promoter regions of Btnl genes. Reexpression of BTNL1 and BTNL6 in cancer cells increased γδIEL survival and activation in coculture assays but failed to augment their cancer-killing ability in vitro or their recruitment to orthotopic tumors. However, inhibition of ß-catenin signaling via genetic deletion of Bcl9/Bcl9L in either Apc-deficient or mutant ß-catenin mouse models restored Hnf4a, Hnf4g, and Btnl gene expression and γδ T-cell infiltration into tumors. These observations highlight an immune-evasion mechanism specific to WNT-driven colon cancer cells that disrupts γδIEL immunosurveillance and furthers cancer progression.
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Neoplasias del Colon , Linfocitos Intraepiteliales , Ratones , Animales , Humanos , beta Catenina/genética , beta Catenina/metabolismo , Linfocitos Intraepiteliales/metabolismo , Butirofilinas/genética , Butirofilinas/metabolismo , Neoplasias del Colon/genética , Receptores de Antígenos de Linfocitos T gamma-delta/genética , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Microambiente TumoralRESUMEN
It is well established that mutations in the canonical WNT-signalling pathway play a major role in various cancers. Critical to developing new therapeutic strategies is understanding which cancers are driven by WNT pathway activation and at what level these mutations occur within the pathway. Some cancers harbour mutations in genes whose protein products operate at the receptor level of the WNT pathway. For instance, tumours with RNF43 or RSPO mutations, still require exogenous WNT ligands to drive WNT signalling (ligand-dependent mutations). Conversely, mutations within the cytoplasmic segment of the Wnt pathway, such as in APC and CTNNB1, lead to constitutive WNT pathway activation even in the absence of WNT ligands (ligand-independent). Here, we review the predominant driving mutations found in cancer that lead to WNT pathway activation, as well as explore some of the therapeutic interventions currently available against tumours harbouring either ligand-dependent or ligand-independent mutations. Finally, we discuss a potentially new therapeutic avenue by targeting the translational apparatus downstream from WNT signalling.
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Neoplasias , Vía de Señalización Wnt , Humanos , Vía de Señalización Wnt/genética , Ligandos , Neoplasias/genética , Neoplasias/terapia , Neoplasias/metabolismo , Mutación/genéticaRESUMEN
BACKGROUND: Teprotumumab is the first treatment for thyroid eye disease (TED), a debilitating autoinflammatory condition, approved by the Food and Drug Administration in the United States, which reduces proptosis and improves quality of life. In the absence of guidelines, clinical recommendations were developed for using teprotumumab in patients with TED in the United States. METHODS: A 3-round modified-Delphi panel was conducted between October 2020 and February 2021 with experts in the management of patients with TED. Key areas regarding the use of teprotumumab were investigated, including eligible patient populations, concomitant treatments, and assessment of response and adverse events. This used 2 survey rounds via an online questionnaire, where statements were scored using 9-point Likert scales. Statements with conflict were included in the third round, involving a consensus meeting via videoconference. RESULTS: Consensus was obtained for all statements (n = 75); of which, 56% were revised to enable agreement of the group. The consensus meeting provided agreement regarding which populations should receive teprotumumab therapy, including all adult patients with TED with a clinical activity score of ≥4. Treatment with teprotumumab can also be considered for TED patients displaying the following characteristics: a CAS of <3, lid retraction of ≥2, and mild or early optic neuropathy with close clinical observation. Further recommendations included suitability of treatment for those beyond 16 months following the initial diagnosis of TED, low CAS concomitant treatment with steroids in some cases, retreatment for those who have relapses, and finally a recommendation to continue therapy for all 8 infusions despite the lack of response by the fourth infusion. CONCLUSIONS: This work constitutes the first consensus on guidelines for the use of teprotumumab. The modified Delphi approach involved physicians with significant experience with the clinical use of teprotumumab, and recommendations were based on current evidence.
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Oftalmopatía de Graves , Adulto , Anticuerpos Monoclonales Humanizados/uso terapéutico , Consenso , Oftalmopatía de Graves/diagnóstico , Oftalmopatía de Graves/tratamiento farmacológico , Humanos , Calidad de VidaRESUMEN
The conceptual origins of ribosome specialization can be traced back to the earliest days of molecular biology. Yet, this field has only recently begun to gather momentum, with numerous studies identifying distinct heterogeneous ribosome populations across multiple species and model systems. It is proposed that some of these compositionally distinct ribosomes may be functionally specialized and able to regulate the translation of specific mRNAs. Identification and functional characterization of specialized ribosomes has the potential to elucidate a novel layer of gene expression control, at the level of translation, where the ribosome itself is a key regulatory player. In this review, we discuss different sources of ribosome heterogeneity, evidence for ribosome specialization, and also the future directions of this exciting field.
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Biosíntesis de Proteínas , Proteínas Ribosómicas , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Ribosómico/metabolismo , Proteínas Ribosómicas/metabolismo , Ribosomas/genética , Ribosomas/metabolismoRESUMEN
Increased protein synthesis supports the rapid cell proliferation associated with cancer. The Rpl24Bst mutant mouse reduces the expression of the ribosomal protein RPL24 and has been used to suppress translation and limit tumorigenesis in multiple mouse models of cancer. Here, we show that Rpl24Bst also suppresses tumorigenesis and proliferation in a model of colorectal cancer (CRC) with two common patient mutations, Apc and Kras. In contrast to previous reports, Rpl24Bst mutation has no effect on ribosomal subunit abundance but suppresses translation elongation through phosphorylation of eEF2, reducing protein synthesis by 40% in tumour cells. Ablating eEF2 phosphorylation in Rpl24Bst mutant mice by inactivating its kinase, eEF2K, completely restores the rates of elongation and protein synthesis. Furthermore, eEF2K activity is required for the Rpl24Bst mutant to suppress tumorigenesis. This work demonstrates that elevation of eEF2 phosphorylation is an effective means to suppress colorectal tumorigenesis with two driver mutations. This positions translation elongation as a therapeutic target in CRC, as well as in other cancers where the Rpl24Bst mutation has a tumour suppressive effect in mouse models.
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Neoplasias Colorrectales/genética , Quinasa del Factor 2 de Elongación/metabolismo , Mutación , Proteínas Ribosómicas/genética , Transducción de Señal , Animales , Modelos Animales de Enfermedad , Femenino , Masculino , Ratones , Ratones Transgénicos , Fosforilación , Proteínas Ribosómicas/metabolismoRESUMEN
Oncogenic KRAS mutations and inactivation of the APC tumor suppressor co-occur in colorectal cancer (CRC). Despite efforts to target mutant KRAS directly, most therapeutic approaches focus on downstream pathways, albeit with limited efficacy. Moreover, mutant KRAS alters the basal metabolism of cancer cells, increasing glutamine utilization to support proliferation. We show that concomitant mutation of Apc and Kras in the mouse intestinal epithelium profoundly rewires metabolism, increasing glutamine consumption. Furthermore, SLC7A5, a glutamine antiporter, is critical for colorectal tumorigenesis in models of both early- and late-stage metastatic disease. Mechanistically, SLC7A5 maintains intracellular amino acid levels following KRAS activation through transcriptional and metabolic reprogramming. This supports the increased demand for bulk protein synthesis that underpins the enhanced proliferation of KRAS-mutant cells. Moreover, targeting protein synthesis, via inhibition of the mTORC1 regulator, together with Slc7a5 deletion abrogates the growth of established Kras-mutant tumors. Together, these data suggest SLC7A5 as an attractive target for therapy-resistant KRAS-mutant CRC.
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Neoplasias Colorrectales/genética , Transportador de Aminoácidos Neutros Grandes 1/metabolismo , Mutación/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Regiones no Traducidas 5'/genética , Sistema de Transporte de Aminoácidos ASC/metabolismo , Animales , Carcinogénesis/patología , Proliferación Celular , Neoplasias Colorrectales/patología , Regulación Neoplásica de la Expresión Génica , Glutamina/metabolismo , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Estimación de Kaplan-Meier , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Ratones Endogámicos C57BL , Antígenos de Histocompatibilidad Menor/metabolismo , Metástasis de la Neoplasia , Oncogenes , ARN Mensajero/genética , ARN Mensajero/metabolismo , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
KRAS-mutant colorectal cancers are resistant to therapeutics, presenting a significant problem for â¼40% of cases. Rapalogs, which inhibit mTORC1 and thus protein synthesis, are significantly less potent in KRAS-mutant colorectal cancer. Using Kras-mutant mouse models and mouse- and patient-derived organoids, we demonstrate that KRAS with G12D mutation fundamentally rewires translation to increase both bulk and mRNA-specific translation initiation. This occurs via the MNK/eIF4E pathway culminating in sustained expression of c-MYC. By genetic and small-molecule targeting of this pathway, we acutely sensitize KRASG12D models to rapamycin via suppression of c-MYC. We show that 45% of colorectal cancers have high signaling through mTORC1 and the MNKs, with this signature correlating with a 3.5-year shorter cancer-specific survival in a subset of patients. This work provides a c-MYC-dependent cotargeting strategy with remarkable potency in multiple Kras-mutant mouse models and metastatic human organoids and identifies a patient population that may benefit from its clinical application. SIGNIFICANCE: KRAS mutation and elevated c-MYC are widespread in many tumors but remain predominantly untargetable. We find that mutant KRAS modulates translation, culminating in increased expression of c-MYC. We describe an effective strategy targeting mTORC1 and MNK in KRAS-mutant mouse and human models, pathways that are also commonly co-upregulated in colorectal cancer.This article is highlighted in the In This Issue feature, p. 995.
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Neoplasias Colorrectales/genética , Factor 4E Eucariótico de Iniciación/efectos de los fármacos , Péptidos y Proteínas de Señalización Intracelular/efectos de los fármacos , Inhibidores mTOR/farmacología , Proteínas Serina-Treonina Quinasas/efectos de los fármacos , Animales , Neoplasias Colorrectales/metabolismo , Modelos Animales de Enfermedad , Factor 4E Eucariótico de Iniciación/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Ratones , Ratones Endogámicos C57BL , Fosforilación , Proteínas Serina-Treonina Quinasas/metabolismoRESUMEN
In this study, the potential sources, scavenging processes, and emission regions for Hg in wet deposition were investigated in rural (Jeju), suburban (Gwangju), and urban sites (Incheon and Seoul) of South Korea. The annual volume-weighted mean concentrations of Hg in wet deposition were four to five times higher in Incheon (16.6 ng L-1) and Seoul (22.5 ng L-1) than in Jeju (4.0 ng L-1) and Gwangju (4.1 ng L-1). The variations in the Hg concentrations in wet deposition of Jeju and Gwangju were related to Cl-, Na+, Mg2+, and K+ originating from marine and crustal sources, and those in Incheon and Seoul were related to SO42-, NO3-, and NH4+ emitted from anthropogenic sources. The below-cloud scavenging was considered a major inclusion process of Hg in Jeju and Gwangju, while the within-cloud scavenging was suggested in Incheon and Seoul, based on the results of correlation analysis with Hg and major ions in wet deposition, and meteorological data. The cluster analysis of backward trajectories demonstrated that the Hg concentration in wet deposition was highest in the cluster transported from Hebei and Shandong of China in Gwangju, but in Seoul, the Hg concentrations of each cluster were comparable. This suggests that regional transport is the major source of Hg in the wet deposition of Gwangju while local transport provides substantial amount of Hg in the wet deposition of Seoul. This was further supported by the results of concentration-weighted trajectories: the most probable source region was east China for Gwangju, and the mid-west of South Korea and east China for Seoul. It is noted that the peak methylmercury concentrations were found every spring with simultaneous increases in atmospheric Al, Ca, Mg, and Fe concentrations, indicating a concurrence with Asian dust. The formation process of methylmercury in Asian dust should be confirmed in future studies.
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Oxidative phosphorylation (OXPHOS) defects caused by somatic mitochondrial DNA (mtDNA) mutations increase with age in human colorectal epithelium and are prevalent in colorectal tumours, but whether they actively contribute to tumorigenesis remains unknown. Here we demonstrate that mtDNA mutations causing OXPHOS defects are enriched during the human adenoma/carcinoma sequence, suggesting they may confer a metabolic advantage. To test this we deleted the tumour suppressor Apc in OXPHOS deficient intestinal stem cells in mice. The resulting tumours were larger than in control mice due to accelerated cell proliferation and reduced apoptosis. We show that both normal crypts and tumours undergo metabolic remodelling in response to OXPHOS deficiency by upregulating the de novo serine synthesis pathway (SSP). Moreover, normal human colonic crypts upregulate the SSP in response to OXPHOS deficiency prior to tumorigenesis. Our data show that age-associated OXPHOS deficiency causes metabolic remodelling that can functionally contribute to accelerated intestinal cancer development.
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Neoplasias Intestinales , Enfermedades Mitocondriales , Animales , Transformación Celular Neoplásica/genética , ADN Mitocondrial/genética , Neoplasias Intestinales/genética , Ratones , Mitocondrias/genética , MutaciónRESUMEN
Audience: The primary audience for this simulation exercise is emergency medicine (EM) residents, although it could be more broadly applied to all provider groups, including medical students, advanced practice providers, and faculty physicians. Introduction: Over the course of their professional careers, approximately 10-15% of physicians will misuse or abuse alcohol or drugs.1 Unfortunately, Emergency Physicians (EPs) are not immune to this phenomenon, and although EPs make up only 4.7% of the active physician workforce,2 they are over-represented in samples of physicians referred to physician health programs (PHPs) for substance use disorder.3 Despite this increased prevalence, when EPs were referred to a PHP by themselves, family, or colleagues, 84% of them completed the program and were practicing medicine 5 years later,3 which makes recognition and referral of the impaired physician an important step to provide the treatment needed for recovery and ultimately for return to practice. Given the prevalence of substance use disorder in EPs, it is not surprising that the 2019 Accreditation Council for Graduate Medical Education (ACGME) Common Program Requirements in Emergency Medicine stipulate that "residents and faculty members must demonstrate an understanding of their personal role in the recognition of impairment, including from illness, fatigue, and substance use, in themselves, their peers, and other members of the health care team."4 Furthermore, the common program requirements also outline that each residency program must have "designated individuals responsible for reporting impaired providers in accordance with each institution's policies as well as being knowledgeable in the resources available to said provider."4 Despite these requirements, there are no best practices available to outline how residency programs can effectively teach trainees how to recognize and report the impairment. This simulation scenario is intended to provide an opportunity for learners to recognize an impaired colleague in a clinical setting, remove them from the clinical care environment, and notify the appropriate contacts, such as a Program Director, Department Chair, or nursing supervisor. To our knowledge, this is the first described simulation scenario where learners develop competency in recognizing and reporting the impaired provider. Objectives: By the end of this simulation, learners will be able to: 1) Identify potential impairment in the form of alcohol intoxication in a physician colleague; 2) demonstrate the ability to communicate effectively with the colleague and remove them from the patient care environment; 3) discuss the appropriate next steps in identifying long-term wellness resources for the impaired colleague; and 4) demonstrate understanding of the need to continue to provide care for the patients by moving the case forward. Educational Methods: This scenario is a simulated encounter taking place in the emergency department (ED) where the patient is a trauma activation who is not critically ill; the learner's confederate colleague in the scenario arrives for sign-out smelling of alcohol and appearing intoxicated. The learner will need to both provide care for the injured patient while addressing their colleague's impairment and safely removing them from the patient care area. Research Methods: The effectiveness of this simulated scenario as a teaching instrument was evaluated utilizing an internally developed evaluation survey that is part of the standard simulation curriculum at West Virginia University (WVU). The survey consisted of questions both regarding the effectiveness of the instructors as well as of the simulation, rated on a Likert scale. Learners were given the opportunity to answer free response questions where they were asked to reflect upon their experience, including the strengths of the experience and any identified opportunities for improvement. Results: Using a standard Likert scale, learners completing the impaired provider simulation scenario reviewed the effectiveness of the simulation and instructors very positively, with the vast majority of learners scoring all aspects of the scenario either as a 4 or 5. The free response answers were universally positive with many participants considering the experience very useful for training on a topic that is not frequently taught in other portions of the formal didactic curriculum. Discussion: While it is fortunately rare to encounter a colleague who is acutely intoxicated by alcohol or drugs and to simultaneously be responsible for providing patient care, it is important that learners are provided with formal instruction on how to recognize impairment and navigate the potentially difficult conversation with the impaired provider to ensure patient safety. This simulated scenario provides a realistic curricular instrument that could be implemented in any EM training program. Topics: Substance abuse; impaired provider; impaired provider reporting policies; professionalism; patient safety; provider safety.
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The Gulf of Mexico region has important sources of acid rain precursors, located in all of the countries; U.S., Mexico and Cuba, and so it is very important to study the chemical composition of the wet atmospheric deposition in all coastal areas. For many years along the U.S. Gulf Coast, acidic precipitation has been measured. Measurements along the Mexican Gulf Coast were begun in 2003. The aim of this study was to evaluate pH, sulfate, nitrate and ammonium concentrations in wet atmospheric deposition, collected daily from 2003 to 2015 at La Mancha (LM), Veracruz and compare the values with the National Atmospheric Deposition Program (NADP) sampling sites located along the U.S. coast of the Gulf of Mexico. The annual Volume Weighted Mean (VWM) pH in wet deposition at La Mancha site ranged from 4.81 to 5.40, which is similar to the U.S. Gulf sites. Additionally, the annual VWM SO42- concentration was from 15 to 31⯵eq/L, which is higher than the U.S. sites. Annual VWM NO3- concentrations were from of 3.5 to 15⯵eq/L, which is lower than all the U.S. sites. At the Mexican site, the SO42-/NO3- ratio was 4.90 and higher than all of the U.S. sites, which were between 1.03 and 2.38. For LM, the median NH4+/NO3- ratio was 0.77, similar to the Florida sites (0.53-0.91), and below the values measured for Louisiana and Texas (1.07-1.5). The Hybrid Single Particle Lagrangian Integrated Trajectory Model (HYSPLIT) was applied in order to identify the emission sources for the pollutants seen at LM. Trajectories showed an important transport to LM from the East (open water) during the rainy season. The region located East of La Mancha shows offshore petroleum operations as sources of acid rain precursors and deposition of acidifying and nitrogen containing compounds. It is important to consider the sulfur dioxide emission sources in the Mexico Gulf region, and to extend the atmospheric deposition sampling to other sites along the Mexican Gulf coast and Cuba.
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Oncogene activation and loss of tumor suppressor function changes the metabolic activity of cancer cells to drive unrestricted proliferation. Moreover, cancer cells adapt their metabolism to sustain growth and survival when access to oxygen and nutrients is restricted, such as in poorly vascularized tumor areas. We show here that p53-deficient colon cancer cells exposed to tumor-like metabolic stress in spheroid culture activated the mevalonate pathway to promote the synthesis of ubiquinone. This was essential to maintain mitochondrial electron transport for respiration and pyrimidine synthesis in metabolically compromised environments. Induction of mevalonate pathway enzyme expression in the absence of p53 was mediated by accumulation and stabilization of mature SREBP2. Mevalonate pathway inhibition by statins blocked pyrimidine nucleotide biosynthesis and induced oxidative stress and apoptosis in p53-deficient cancer cells in spheroid culture. Moreover, ubiquinone produced by the mevalonate pathway was essential for the growth of p53-deficient tumor organoids. In contrast, inhibition of intestinal hyperproliferation by statins in an Apc/KrasG12D-mutant mouse model was independent of de novo pyrimidine synthesis. Our results highlight the importance of the mevalonate pathway for maintaining mitochondrial electron transfer and biosynthetic activity in cancer cells exposed to metabolic stress. They also demonstrate that the metabolic output of this pathway depends on both genetic and environmental context. SIGNIFICANCE: These findings suggest that p53-deficient cancer cells activate the mevalonate pathway via SREBP2 and promote the synthesis of ubiquinone that plays an essential role in reducing oxidative stress and supports the synthesis of pyrimidine nucleotide.
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Ácido Mevalónico/metabolismo , Neoplasias/patología , Pirimidinas/metabolismo , Proteína 2 de Unión a Elementos Reguladores de Esteroles/metabolismo , Ubiquinona/análogos & derivados , Animales , Apoptosis , Línea Celular Tumoral , Supervivencia Celular , Ciclo del Ácido Cítrico/efectos de los fármacos , Ciclo del Ácido Cítrico/genética , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Mucosa Intestinal/citología , Mucosa Intestinal/patología , Ratones , Ratones Transgénicos , Neoplasias/genética , Neoplasias/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Estrés Fisiológico , Microambiente Tumoral/genética , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Ubiquinona/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Tumours depend on altered rates of protein synthesis for growth and survival, which suggests that mechanisms controlling mRNA translation may be exploitable for therapy. Here, we show that loss of APC, which occurs almost universally in colorectal tumours, strongly enhances the dependence on the translation initiation factor eIF2B5. Depletion of eIF2B5 induces an integrated stress response and enhances translation of MYC via an internal ribosomal entry site. This perturbs cellular amino acid and nucleotide pools, strains energy resources and causes MYC-dependent apoptosis. eIF2B5 limits MYC expression and prevents apoptosis in APC-deficient murine and patient-derived organoids and in APC-deficient murine intestinal epithelia in vivo. Conversely, the high MYC levels present in APC-deficient cells induce phosphorylation of eIF2α via the kinases GCN2 and PKR. Pharmacological inhibition of GCN2 phenocopies eIF2B5 depletion and has therapeutic efficacy in tumour organoids, which demonstrates that a negative MYC-eIF2α feedback loop constitutes a targetable vulnerability of colorectal tumours.
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Neoplasias Colorrectales/genética , Factor 2 Eucariótico de Iniciación/genética , Regulación Neoplásica de la Expresión Génica , Proteínas Serina-Treonina Quinasas/genética , Proteínas Proto-Oncogénicas c-myc/genética , Proteína de la Poliposis Adenomatosa del Colon/genética , Proteína de la Poliposis Adenomatosa del Colon/metabolismo , Animales , Apoptosis/genética , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Colon/metabolismo , Colon/patología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Factor 2 Eucariótico de Iniciación/metabolismo , Factor 2B Eucariótico de Iniciación/antagonistas & inhibidores , Factor 2B Eucariótico de Iniciación/genética , Factor 2B Eucariótico de Iniciación/metabolismo , Retroalimentación Fisiológica , Femenino , Células HCT116 , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Biosíntesis de Proteínas , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Transducción de Señal , Análisis de Supervivencia , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The original version of this Article contained an error in the spelling of the author Miryam Müller, which was incorrectly given as Miryam Müeller. This has now been corrected in both the PDF and HTML versions of the Article.
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Different thresholds of Wnt signalling are thought to drive stem cell maintenance, regeneration, differentiation and cancer. However, the principle that oncogenic Wnt signalling could be specifically targeted remains controversial. Here we examine the requirement of BCL9/9l, constituents of the Wnt-enhanceosome, for intestinal transformation following loss of the tumour suppressor APC. Although required for Lgr5+ intestinal stem cells and regeneration, Bcl9/9l deletion has no impact upon normal intestinal homeostasis. Loss of BCL9/9l suppressed many features of acute APC loss and subsequent Wnt pathway deregulation in vivo. This resulted in a level of Wnt pathway activation that favoured tumour initiation in the proximal small intestine (SI) and blocked tumour growth in the colon. Furthermore, Bcl9/9l deletion completely abrogated ß-catenin driven intestinal and hepatocellular transformation. We speculate these results support the just-right hypothesis of Wnt-driven tumour formation. Importantly, loss of BCL9/9l is particularly effective at blocking colonic tumourigenesis and mutations that most resemble those that occur in human cancer.