The autophagy-targeting compound V46 enhances antimicrobial responses to Mycobacteroides abscessus by activating transcription factor EB.

Mycobacteroides abscessus (Mabc) is a rapidly growing nontuberculous mycobacterium that poses a considerable challenge as a multidrug-resistant pathogen causing chronic human infection. Effective therapeutics that enhance protective immune responses to Mabc are urgently needed. This study introduces trans-3,5,4'-trimethoxystilbene (V46), a novel resveratrol analogue with autophagy-activating properties and antimicrobial activity against Mabc infection, including multidrug-resistant strains. Among the resveratrol analogues tested, V46 significantly inhibited the growth of both rough and smooth Mabc strains, including multidrug-resistant strains, in macrophages and in the lungs of mice infected with Mabc. Additionally, V46 substantially reduced Mabc-induced levels of pro-inflammatory cytokines and chemokines in both macrophages and during in vivo infection. Mechanistic analysis showed that V46 suppressed the activation of the protein kinase B/Akt-mammalian target of rapamycin signaling pathway and enhanced adenosine monophosphate-activated protein kinase signaling in Mabc-infected cells. Notably, V46 activated autophagy and the nuclear translocation of transcription factor EB, which is crucial for antimicrobial host defenses against Mabc. Furthermore, V46 upregulated genes associated with autophagy and lysosomal biogenesis in Mabc-infected bone marrow-derived macrophages. The combination of V46 and rifabutin exerted a synergistic antimicrobial effect. These findings identify V46 as a candidate host-directed therapeutic for Mabc infection that activates autophagy and lysosomal function via transcription factor EB.

Metabolic stress induces a double-positive feedback loop between AMPK and SQSTM1/p62 conferring dual activation of AMPK and NFE2L2/NRF2 to synergize antioxidant defense.

Co-occurring mutations in KEAP1 in STK11/LKB1-mutant NSCLC activate NFE2L2/NRF2 to compensate for the loss of STK11-AMPK activity during metabolic adaptation. Characterizing the regulatory crosstalk between the STK11-AMPK and KEAP1-NFE2L2 pathways during metabolic stress is crucial for understanding the implications of co-occurring mutations. Here, we found that metabolic stress increased the expression and phosphorylation of SQSTM1/p62, which is essential for the activation of NFE2L2 and AMPK, synergizing antioxidant defense and tumor growth. The SQSTM1-driven dual activation of NFE2L2 and AMPK was achieved by inducing macroautophagic/autophagic degradation of KEAP1 and facilitating the AXIN-STK11-AMPK complex formation on the lysosomal membrane, respectively. In contrast, the STK11-AMPK activity was also required for metabolic stress-induced expression and phosphorylation of SQSTM1, suggesting a double-positive feedback loop between AMPK and SQSTM1. Mechanistically, SQSTM1 expression was increased by the PPP2/PP2A-dependent dephosphorylation of TFEB and TFE3, which was induced by the lysosomal deacidification caused by low glucose metabolism and AMPK-dependent proton reduction. Furthermore, SQSTM1 phosphorylation was increased by MAP3K7/TAK1, which was activated by ROS and pH-dependent secretion of lysosomal Ca2+. Importantly, phosphorylation of SQSTM1 at S24 and S226 was critical for the activation of AMPK and NFE2L2. Notably, the effects caused by metabolic stress were abrogated by the protons provided by lactic acid. Collectively, our data reveal a novel double-positive feedback loop between AMPK and SQSTM1 leading to the dual activation of AMPK and NFE2L2, potentially explaining why co-occurring mutations in STK11 and KEAP1 happen and providing promising therapeutic strategies for lung cancer.Abbreviations: AMPK: AMP-activated protein kinase; BAF1: bafilomycin A1; ConA: concanamycin A; DOX: doxycycline; IP: immunoprecipitation; KEAP1: kelch like ECH associated protein 1; LN: low nutrient; MAP3K7/TAK1: mitogen-activated protein kinase kinase kinase 7; MCOLN1/TRPML1: mucolipin TRP cation channel 1; MEFs: mouse embryonic fibroblasts; MTORC1: mechanistic target of rapamycin kinase complex 1; NAC: N-acetylcysteine; NFE2L2/NRF2: NFE2 like bZIP transcription factor 2; NSCLC: non-small cell lung cancer; PRKAA/AMPKα: protein kinase AMP-activated catalytic subunit alpha; PPP2/PP2A: protein phosphatase 2; ROS: reactive oxygen species; PPP3/calcineurin: protein phosphatase 3; RPS6KB1/p70S6K: ribosomal protein S6 kinase B1; SQSTM1/p62: sequestosome 1; STK11/LKB1: serine/threonine kinase 11; TCL: total cell lysate; TFEB: transcription factor EB; TFE3: transcription factor binding to IGHM enhancer 3; V-ATPase: vacuolar-type H+-translocating ATPase.

Deep Learning-based Assessment of Facial Asymmetry Using U-Net Deep Convolutional Neural Network Algorithm.

OBJECTIVES: This study aimed to evaluate the diagnostic performance of a deep convolutional neural network (DCNN)-based computer-assisted diagnosis (CAD) system to detect facial asymmetry on posteroanterior (PA) cephalograms and compare the results of the DCNN with those made by the orthodontist. MATERIALS AND METHODS: PA cephalograms of 1020 patients with orthodontics were used to train the DCNN-based CAD systems for autoassessment of facial asymmetry, the degree of menton deviation, and the coordinates of its regarding landmarks. Twenty-five PA cephalograms were used to test the performance of the DCNN in analyzing facial asymmetry. The diagnostic performance of the DCNN-based CAD system was assessed using independent t -tests and Bland-Altman plots. RESULTS: Comparison between the DCNN-based CAD system and conventional analysis confirmed no significant differences. Bland-Altman plots showed good agreement for all the measurements. CONCLUSIONS: The DCNN-based CAD system might offer a clinically acceptable diagnostic evaluation of facial asymmetry on PA cephalograms.

Lactate as a major epigenetic carbon source for histone acetylation via nuclear LDH metabolism.

Histone acetylation involves the transfer of two-carbon units to the nucleus that are embedded in low-concentration metabolites. We found that lactate, a high-concentration metabolic byproduct, can be a major carbon source for histone acetylation through oxidation-dependent metabolism. Both in cells and in purified nuclei, 13C3-lactate carbons are incorporated into histone H4 (maximum incorporation: ~60%). In the purified nucleus, this process depends on nucleus-localized lactate dehydrogenase (LDHA), knockout (KO) of which abrogates incorporation. Heterologous expression of nucleus-localized LDHA reverses the KO effect. Lactate itself increases histone acetylation, whereas inhibition of LDHA reduces acetylation. In vitro and in vivo settings exhibit different lactate incorporation patterns, suggesting an influence on the microenvironment. Higher nuclear LDHA localization is observed in pancreatic cancer than in normal tissues, showing disease relevance. Overall, lactate and nuclear LDHA can be major structural and regulatory players in the metabolism-epigenetics axis controlled by the cell's own status or the environmental status.

Thromboembolic events in patients who received adjuvant chemotherapy for gastric cancer: a single-center retrospective study.

BACKGROUND: Thromboembolic events (TEEs) are significant adverse events that can cause serious morbidities and mortality in cancer patients receiving chemotherapy. Patients with gastric cancer (GC) treated with palliative chemotherapy have been reported to experience a TEE incidence of 5-27%. However, very few reports have addressed TEEs in adjuvant chemotherapy (AC) for GC. METHODS: This study retrospectively analyzed 611 GC patients (stage II: 309, III: 302) who started AC with capecitabine/oxaliplatin (167 patients) or S-1 (444 patients) after undergoing curative resection between January 2013 and June 2020 at a single center. The incidence of TEEs during AC or within 1 year after AC completion was investigated, while analyzing the factors that influenced the TEEs' occurrence. RESULTS: TEEs were confirmed in 20 patients (3.3%), and TEEs occurred in almost all patients in the S-1 group (19 patients). The most common TEE types were cerebral infarction and pulmonary thromboembolism (five patients each). Although old age (≥ 70 years, p < 0.0001), S-1 treatment (p = 0.021), and hypertension (p = 0.017) were identified as significant risk factors for TEEs in univariate analysis, only old age showed a statistically significant correlation with TEEs' occurrence in multivariate analysis (odds ratio: 3.07; 95% confidence interval 1.11-8.48; p = 0.031). CONCLUSIONS: TEEs occurred in fewer patients with GC who had been treated with AC than patients who had received palliative chemotherapy in previous reports. However, elderly GC patients who are undergoing AC require more careful surveillance for possible TEEs, considering relatively higher incidence of them.

Targeting ERRα promotes cytotoxic effects against acute myeloid leukemia through suppressing mitochondrial oxidative phosphorylation.

Acute myeloid leukemia (AML) is an aggressive blood cancer with poor clinical outcomes. Emerging data suggest that mitochondrial oxidative phosphorylation (mtOXPHOS) plays a significant role in AML tumorigenesis, progression, and resistance to chemotherapies. However, how the mtOXPHOS is regulated in AML cells is not well understood. In this study, we investigated the oncogenic functions of ERRα in AML by combining in silico, in vitro, and in vivo analyses and showed ERRα is a key regulator of mtOXPHOS in AML cells. The increased ERRα level was associated with worse clinical outcomes of AML patients. Single cell RNA-Seq analysis of human primary AML cells indicated that ERRα-expressing cancer cells had significantly higher mtOXPHOS enrichment scores. Blockade of ERRα by pharmacologic inhibitor (XCT-790) or gene silencing suppressed mtOXPHOS and increased anti-leukemic effects in vitro and in xenograft mouse models.

Ohmyungsamycin promotes M1-like inflammatory responses to enhance host defence against Mycobacteroides abscessus infections.

Ohmyungsamycin A (OMS) is a newly identified cyclic peptide that exerts antimicrobial effects against Mycobacterium tuberculosis. However, its role in nontuberculous mycobacteria (NTMs) infections has not been clarified. Mycobacteroides abscessus (Mabc) is a rapidly growing NTM that has emerged as a human pathogen in both immunocompetent and immunosuppressed individuals. In this study, we demonstrated that OMS had significant antimicrobial effects against Mabc infection in both immunocompetent and immunodeficient mice, and in macrophages. OMS treatment amplified Mabc-induced expression of M1-related proinflammatory cytokines and inducible nitric oxide synthase, and significantly downregulated arginase-1 expression in murine macrophages. In addition, OMS augmented Mabc-mediated production of mitochondrial reactive oxygen species (mtROS), which promoted M1-like proinflammatory responses in Mabc-infected macrophages. OMS-induced production of mtROS and nitric oxide was critical for OMS-mediated antimicrobial responses during Mabc infections. Notably, the combination of OMS and rifabutin had a synergistic effect on the antimicrobial responses against Mabc infections in vitro, in murine macrophages, and in zebrafish models in vivo. Collectively, these data strongly suggest that OMS may be an effective M1-like adjunctive therapeutic against Mabc infections, either alone or in combination with antibiotics.

Chemical modulation of SQSTM1/p62-mediated xenophagy that targets a broad range of pathogenic bacteria.

The N-degron pathway is a proteolytic system in which the N-terminal degrons (N-degrons) of proteins, such as arginine (Nt-Arg), induce the degradation of proteins and subcellular organelles via the ubiquitin-proteasome system (UPS) or macroautophagy/autophagy-lysosome system (hereafter autophagy). Here, we developed the chemical mimics of the N-degron Nt-Arg as a pharmaceutical means to induce targeted degradation of intracellular bacteria via autophagy, such as Salmonella enterica serovar Typhimurium (S. Typhimurium), Escherichia coli, and Streptococcus pyogenes as well as Mycobacterium tuberculosis (Mtb). Upon binding the ZZ domain of the autophagic cargo receptor SQSTM1/p62 (sequestosome 1), these chemicals induced the biogenesis and recruitment of autophagic membranes to intracellular bacteria via SQSTM1, leading to lysosomal degradation. The antimicrobial efficacy was independent of rapamycin-modulated core autophagic pathways and synergistic with the reduced production of inflammatory cytokines. In mice, these drugs exhibited antimicrobial efficacy for S. Typhimurium, Bacillus Calmette-Guérin (BCG), and Mtb as well as multidrug-resistant Mtb and inhibited the production of inflammatory cytokines. This dual mode of action in xenophagy and inflammation significantly protected mice from inflammatory lesions in the lungs and other tissues caused by all the tested bacterial strains. Our results suggest that the N-degron pathway provides a therapeutic target in host-directed therapeutics for a broad range of drug-resistant intracellular pathogens.Abbreviations: ATG: autophagy-related gene; BCG: Bacillus Calmette-Guérin; BMDMs: bone marrow-derived macrophages; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CFUs: colony-forming units; CXCL: C-X-C motif chemokine ligand; EGFP: enhanced green fluorescent protein; IL1B/IL-1ß: interleukin 1 beta; IL6: interleukin 6; LIR: MAP1LC3/LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; Mtb: Mycobacterium tuberculosis; MTOR: mechanistic target of rapamycin kinase; NBR1: NBR1 autophagy cargo receptor; OPTN: optineurin; PB1: Phox and Bem1; SQSTM1/p62: sequestosome 1; S. Typhimurium: Salmonella enterica serovar Typhimurium; TAX1BP1: Tax1 binding protein 1; TNF: tumor necrosis factor; UBA: ubiquitin-associated.

A non-catalytic scaffolding activity of hexokinase 2 contributes to EMT and metastasis.

Hexokinase 2 (HK2), which catalyzes the first committed step in glucose metabolism, is induced in cancer cells. HK2's role in tumorigenesis has been attributed to its glucose kinase activity. Here, we describe a kinase independent HK2 activity, which contributes to metastasis. HK2 binds and sequesters glycogen synthase kinase 3 (GSK3) and acts as a scaffold forming a ternary complex with the regulatory subunit of protein kinase A (PRKAR1a) and GSK3ß to facilitate GSK3ß phosphorylation and inhibition by PKA. Thus, HK2 functions as an A-kinase anchoring protein (AKAP). Phosphorylation by GSK3ß targets proteins for degradation. Consistently, HK2 increases the level and stability of GSK3 targets, MCL1, NRF2, and particularly SNAIL. In addition to GSK3 inhibition, HK2 kinase activity mediates SNAIL glycosylation, which prohibits its phosphorylation by GSK3. Finally, in mouse models of breast cancer metastasis, HK2 deficiency decreases SNAIL protein levels and inhibits SNAIL-mediated epithelial mesenchymal transition and metastasis.

Mitofusin-2 boosts innate immunity through the maintenance of aerobic glycolysis and activation of xenophagy in mice.

Mitochondrial function and innate immunity are intimately linked; however, the mechanisms how mitochondrion-shaping proteins regulate innate host defense remains largely unknown. Herein we show that mitofusin-2 (MFN2), a mitochondrial fusion protein, promotes innate host defense through the maintenance of aerobic glycolysis and xenophagy via hypoxia-inducible factor (HIF)-1α during intracellular bacterial infection. Myeloid-specific MFN2 deficiency in mice impaired the antimicrobial and inflammatory responses against mycobacterial and listerial infection. Mechanistically, MFN2 was required for the enhancement of inflammatory signaling through optimal induction of aerobic glycolysis via HIF-1α, which is activated by mitochondrial respiratory chain complex I and reactive oxygen species, in macrophages. MFN2 did not impact mitophagy during infection; however, it promoted xenophagy activation through HIF-1α. In addition, MFN2 interacted with the late endosomal protein Rab7, to facilitate xenophagy during mycobacterial infection. Our findings reveal the mechanistic regulations by which MFN2 tailors the innate host defense through coordinated control of immunometabolism and xenophagy via HIF-1α during bacterial infection.

NRF2 Activation Promotes Aggressive Lung Cancer and Associates with Poor Clinical Outcomes.

PURPOSE: Stabilization of the transcription factor NRF2 through genomic alterations in KEAP1 and NFE2L2 occurs in a quarter of patients with lung adenocarcinoma and a third of patients with lung squamous cell carcinoma. In lung adenocarcinoma, KEAP1 loss often co-occurs with STK11 loss and KRAS-activating alterations. Despite its prevalence, the impact of NRF2 activation on tumor progression and patient outcomes is not fully defined. EXPERIMENTAL DESIGN: We model NRF2 activation, STK11 loss, and KRAS activation in vivo using novel genetically engineered mouse models. Furthermore, we derive a NRF2 activation signature from human non-small cell lung tumors that we use to dissect how these genomic events impact outcomes and immune contexture of participants in the OAK and IMpower131 immunotherapy trials. RESULTS: Our in vivo data reveal roles for NRF2 activation in (i) promoting rapid-onset, multifocal intrabronchiolar carcinomas, leading to lethal pulmonary dysfunction, and (ii) decreasing elevated redox stress in KRAS-mutant, STK11-null tumors. In patients with nonsquamous tumors, the NRF2 signature is negatively prognostic independently of STK11 loss. Patients with lung squamous cell carcinoma with low NRF2 signature survive longer when receiving anti-PD-L1 treatment. CONCLUSIONS: Our in vivo modeling establishes NRF2 activation as a critical oncogenic driver, cooperating with STK11 loss and KRAS activation to promote aggressive lung adenocarcinoma. In patients, oncogenic events alter the tumor immune contexture, possibly having an impact on treatment responses. Importantly, patients with NRF2-activated nonsquamous or squamous tumors have poor prognosis and show limited response to anti-PD-L1 treatment.

Nuclear Receptors as Autophagy-Based Antimicrobial Therapeutics.

Autophagy is an intracellular process that targets intracellular pathogens for lysosomal degradation. Autophagy is tightly controlled at transcriptional and post-translational levels. Nuclear receptors (NRs) are a family of transcriptional factors that regulate the expression of gene sets involved in, for example, metabolic and immune homeostasis. Several NRs show promise as host-directed anti-infectives through the modulation of autophagy activities by their natural ligands or small molecules (agonists/antagonists). Here, we review the roles and mechanisms of NRs (vitamin D receptors, estrogen receptors, estrogen-related receptors, and peroxisome proliferator-activated receptors) in linking immunity and autophagy during infection. We also discuss the potential of emerging NRs (REV-ERBs, retinoic acid receptors, retinoic acid-related orphan receptors, liver X receptors, farnesoid X receptors, and thyroid hormone receptors) as candidate antimicrobials. The identification of novel roles and mechanisms for NRs will enable the development of autophagy-adjunctive therapeutics for emerging and re-emerging infectious diseases.

Sirtuin 3 is essential for host defense against Mycobacterium abscessus infection through regulation of mitochondrial homeostasis.

The global incidence of Mycobacterium abscessus (Mabc), a rapidly growing nontuberculous mycobacterial strain that causes treatment-refractory pulmonary diseases, is increasing. Despite this, the host factors that allow for protection against infection are largely unknown. In this study, we found that sirtuin 3 (SIRT3), a mitochondrial protein deacetylase, plays a critical role in host defense against Mabc infection. Mabc decreased SIRT3 and upregulated mitochondrial oxidative stress in macrophages. SIRT3 deficiency led to increased bacterial loads, histopathological, and mitochondrial damage, and pathological inflammation during Mabc infection. Administration of scavengers of mitochondrial reactive oxygen species significantly decreased the in vivo Mabc burden and excessive inflammation, and induced SIRT3 expression in infected lungs. Notably, SIRT3 agonist (resveratrol) significantly decreased Mabc growth and attenuated inflammation in mice and zebrafishes, indicating the key role for SIRT3 in metazoan host defense. Collectively, these data strongly suggest that SIRT3 is a host-directed therapeutic target against Mabc infection by controlling mitochondrial homeostasis.

Diol-ginsenosides from Korean Red Ginseng delay the development of type 1 diabetes in diabetes-prone biobreeding rats.

BACKGROUND: The effects of diol-ginsenoside fraction (Diol-GF) and triol-ginsenoside fraction (Triol-GF) from Korean Red Ginseng on the development of type 1 diabetes (T1D) were examined in diabetes-prone biobreeding (DP-BB) rats that spontaneously develop T1D through an autoimmune process. METHODS: DP-BB female rats were treated with Diol-GF or Triol-GF daily from the age of 3-4 weeks up to 11-12 weeks (1 mg/g body weight). RESULTS: Diol-GF delayed the onset, and reduced the incidence, of T1D. Islets of Diol-GF-treated DP-BB rats showed significantly lower insulitis and preserved higher plasma and pancreatic insulin levels. Diol-GF failed to change the proportion of lymphocyte subsets such as T cells, natural killer cells, and macrophages in the spleen and blood. Diol-GF had no effect on the ability of DP-BB rat splenocytes to induce diabetes in recipients. Diol-GF and diol-ginsenoside Rb1 significantly decreased tumor necrosis factor α production, whereas diol-ginsenosides Rb1 and Rd decreased interleukin 1ß production in RAW264.7 cells. Furthermore, mixed cytokine- and chemical-induced ß-cell cytotoxicity was greatly inhibited by Diol-GF and diol-ginsenosides Rc and Rd in RIN5mF cells. However, nitric oxide production in RAW264.7 cells was unaffected by diol-ginsenosides. CONCLUSION: Diol-GF, but not Triol-GF, significantly delayed the development of insulitis and T1D in DP-BB rats. The antidiabetogenic action of Diol-GF may result from the decrease in cytokine production and increase in ß-cell resistance to cytokine/free radical-induced cytotoxicity.

NRF2-driven redox metabolism takes center stage in cancer metabolism from an outside-in perspective.

Cancer development is a process of somatic clonal evolution. Darwinian principles of evolution emphasize the interaction between heritable individual variability and selective pressure from the environment. However, the current prevailing concept of cancer evolution mostly focuses on the alterations of genes, signaling, and metabolism inside cells, which underestimates the impact of environmental pressure in selecting the adapted cells. Recently, unsuccessful outcomes and many concerns raised in targeting those alterations inside cells have cast doubt on the current "cell-centric" paradigm of cancer formation, which necessitates a paradigm shift to an outside-in direction that considers environmental changes as a driver in determining the characteristics of selected cells. In the tumor microenvironment, reactive oxygen species (ROS) are one of the most abundant chemical constituents generated by inflammatory and hypoxic conditions. Because of their cytotoxicity when present at high levels, ROS should be the pressure that selects cells with a high capacity for ROS metabolism and antioxidant defense, both of which are referred to as redox metabolism. Cancer genome analyses have found that nuclear factor E2-related factor 2 (NRF2), which plays an indispensable role in redox metabolism, is frequently activated in many types of cancer, particularly lung cancer. This suggests that an ROS-rich microenvironment drives the selection, survival, and growth of cells with high NRF2 activity. Thus, NRF2-driven redox metabolism should be the most crucial part of cancer metabolism, proposing NRF2 inhibitor as an attractive therapeutic target for cancer.

Targeting interleukin-6 as a strategy to overcome stroma-induced resistance to chemotherapy in gastric cancer.

BACKGROUND: Although the tumor stroma in solid tumors like gastric cancer (GC) plays a crucial role in chemo-resistance, specific targets to inhibit the interaction between the stromal and cancer cells have not yet been utilized in clinical practice. The present study aims to determine whether cancer-associated fibroblasts (CAFs), a major component of the tumor stroma, confer chemotherapeutic resistance to GC cells, and to discover potential targets to improve chemo-response in GC. METHODS: To identify CAF-specific proteins and signal transduction pathways affecting chemo-resistance in GC cells, secretome and transcriptome analyses were performed. We evaluated the inhibiting effect of CAF-specific protein in in vivo and in vitro models and investigated the expression of CAF-specific protein in human GC tissues. RESULTS: Secretome and transcriptome data revealed that interleukin-6 (IL-6) is a CAF-specific secretory protein that protects GC cells via paracrine signaling. Furthermore, CAF-induced activation of the Janus kinase 1-signal transducer and activator of transcription 3 signal transduction pathway confers chemo-resistance in GC cells. CAF-mediated inhibition of chemotherapy-induced apoptosis was abrogated by the anti-IL-6 receptor monoclonal antibody tocilizumab in various experimental models. Clinical data revealed that IL-6 was prominently expressed in the stromal portion of GC tissues, and IL-6 upregulation in GC tissues was correlated with poor responsiveness to chemotherapy. CONCLUSIONS: Our data provide plausible evidence for crosstalk between GC cells and CAFs, wherein IL-6 is a key contributor to chemoresistance. These findings suggest the potential therapeutic application of IL-6 inhibitors to enhance the responsiveness to chemotherapy in GC.

Association between glucose-lowering treatment and cancer metastasis among patients with preexisting type 2 diabetes and incident malignancy.

Preclinical data suggested that dipeptidyl peptidase-4 (DPP-4) inhibitors may promote metastatic progression of preexisting cancer via nuclear factor erythroid 2-related factor 2 (NRF2) activation. We aimed to investigate the association between different glucose-lowering treatments, including DPP-4 inhibitors and metformin, both with potential NRF2 modulating effects, and new-onset metastatic cancer among type 2 diabetes patients with comorbid incident cancer. This population-based cohort study included 223,530 diabetic patients newly diagnosed with primary cancer during 2009-2011 in Korea. The patients were categorized into five study cohorts in accordance with treatment modalities during the follow-up until the end of 2016: no-antidiabetic drugs (no-AD), metformin, DPP-4 inhibitors, metformin+DPP-4 inhibitors, and insulin treatment. After propensity score (PS) matching in a 1:1 ratio against the no-AD group, 18,805 patients in metformin, 1,865 in DPP-4 inhibitors, 31,074 in metformin+DPP-4 inhibitors, and 1,895 patients in insulin groups were identified for cohort entry and analyzed against the corresponding number of no-AD patients in each PS-matched comparison pair. Metastatic risk was lower with metformin plus or minus DPP-4 inhibitors (HR 0.84, 95% CI 0.79-0.90 and 0.87, 0.80-0.95, respectively), not significantly associated with DPP-4 inhibitors (0.99, 0.77-1.29) except after thyroid cancer (3.89, 1.01-9.64), and higher with insulin therapy (1.81, 1.46-2.24) compared to no-AD use for all cancers combined. In conclusion, DPP-4 inhibitor therapy was not associated with significant risk of cancer metastasis relative to no-AD therapy, irrespective of patient age and sex, except after thyroid cancer, while metastatic risk was decreased with metformin treatment among type 2 diabetes patients with preexisting cancer.

Author Correction: Hexokinase-2 depletion inhibits glycolysis and induces oxidative phosphorylation in hepatocellular carcinoma and sensitizes to metformin.

In the originally published version of this Article, the colours of the bars in Fig. 4b were inadvertently switched during the production process, such that 'HK2-Dox' and 'HK2+Dox' were depicted in red and 'Nt-Dox' and 'Nt+Dox' were depicted in blue. These errors have now been corrected in both the PDF and HTML versions of the Article.

Exploring vitamin D metabolism and function in cancer.

Vitamin D, traditionally known as an essential nutrient, is a precursor of a potent steroid hormone that regulates a broad spectrum of physiological processes. In addition to its classical roles in bone metabolism, epidemiological, preclinical, and cellular research during the last decades, it revealed that vitamin D may play a key role in the prevention and treatment of many extra-skeletal diseases such as cancer. Vitamin D, as a prohormone, undergoes two-step metabolism in liver and kidney to produce a biologically active metabolite, calcitriol, which binds to the vitamin D receptor (VDR) for the regulation of expression of diverse genes. In addition, recent studies have revealed that vitamin D can also be metabolized and activated through a CYP11A1-driven non-canonical metabolic pathway. Numerous anticancer properties of vitamin D have been proposed, with diverse effects on cancer development and progression. However, accumulating data suggest that the metabolism and functions of vitamin D are dysregulated in many types of cancer, conferring resistance to the antitumorigenic effects of vitamin D and thereby contributing to the development and progression of cancer. Thus, understanding dysregulated vitamin D metabolism and function in cancer will be critical for the development of promising new strategies for successful vitamin D-based cancer therapy.