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Recent studies have pointed to the role of Krüpple‐like factor 12 (KLF12) in cancer‐associated processes, including cancer proliferation, apoptosis, and metastasis. However, the role of KLF12 in tumor immunity remains obscure. Here, we found that KLF12 expression was significantly higher in non‐small cell lung cancer (NSCLC) cells with higher programmed death‐ligand 1 (PD‐L1) expression. Additionally, a positive correlation between KLF12 and PD‐L1 was observed in clinical patient tumor tissues. By chromatin immunoprecipitation (ChIP) analysis, KLF12 was identified to bind to the CACCC motif of the PD‐L1 promoter. Overexpression of KLF12 promoted PD‐L1 transcription, whereas silencing of KLF12 inhibited PD‐L1 transcription. Furthermore, signal transducer and activator of transcription 1 (STAT1)‐ and STAT3‐triggered PD‐L1 transcription was abolished in the absence of KLF12, and KLF12 knockdown weakened the binding of STAT1 and STAT3 to the PD‐L1 promoter. Mechanistically, KLF12 physically interacted with P300, a histone acetyltransferase. In addition, KLF12 silencing reduced P300 binding to the PD‐L1 promoter, which subsequently caused decreased acetylation of histone H3. PD‐L1 transcription driven by KLF12 overexpression was eliminated by EP300 silencing. In immunocompetent mice, KLF12 knockout inhibited tumor growth and promoted infiltration of CD8+ T cells. However, this phenomenon was not observed in immunodeficient mice. Overall, this study reveals KLF12‐mediated transcriptional regulation of PD‐L1 in NSCLC; targeting KLF12 may be a potential therapeutic strategy for NSCLC. [ABSTRACT FROM AUTHOR]

Nephrotoxicity has become prominent due to the increase in the clinical use of nilotinib, a second‐generation BCR‐ABL1 inhibitor in the first‐line treatment of Philadelphia chromosome‐positive chronic myeloid leukemia. To date, the mechanism of nilotinib nephrotoxicity is still unknown, leading to a lack of clinical intervention strategies. Here, it is found that nilotinib could induce glomerular atrophy, renal tubular degeneration, and kidney fibrosis in an animal model. Mechanistically, nilotinib induces intrinsic apoptosis by specifically reducing the level of BCL2 like 1 (Bcl‐XL) in both vascular endothelial cells and renal tubular epithelial cells, as well as in vivo. It is confirmed that chloroquine (CQ) intervenes with nilotinib‐induced apoptosis and improves mitochondrial integrity, reactive oxygen species accumulation, and DNA damage by reversing the decreased Bcl‐XL. The intervention effect is dependent on the alleviation of the nilotinib‐induced reduction in ubiquitin specific peptidase 13 (USP13) and does not rely on autophagy inhibition. Additionally, it is found that USP13 abrogates cell apoptosis by preventing excessive ubiquitin‒proteasome degradation of Bcl‐XL. In conclusion, the research reveals the molecular mechanism of nilotinib's nephrotoxicity, highlighting USP13 as an important regulator of Bcl‐XL stability in determining cell fate, and provides CQ analogs as a clinical intervention strategy for nilotinib's nephrotoxicity. [ABSTRACT FROM AUTHOR]

Drug‐induced liver injury (DILI) has become a significant health care problem worldwide. Centella asiatica (L.) urban was traditionally used to prevent or treat various diseases, yet whether it works on hepatic injury remains unclear. In this study, multiple experimental models with different damage degrees and types of liver injury have been established to evaluate the hepatoprotective effects of an n‐butanol extract of Centella asiatica (CA‐BU). Our results revealed that CA‐BU improved hepatocyte L02 cells survival from H2O2‐induced oxidative damage in a concentration‐dependent manner. We further verified the hepatoprotective effects of CA‐BU in mice models of acetaminophen‐induced acute liver injury (one of the most common DILIs clinically) and CCl4‐induced acute chemical liver injury, and a rat model of chronic alcoholic steatohepatitis. Furthermore, network pharmacology approaches were performed to explore the underlying mechanisms, and we predicted AKT1, EGFR, VEGFA, and STAT3 as the potential therapeutic targets. In follow‐up studies, we will focus on targets verification and provide a deeper insight into the mechanisms of CA‐BU against liver damage. Finally, we hope that these findings will provide new ideas and insights for the treatment of acute or chronic liver injury in the clinic. [ABSTRACT FROM AUTHOR]

Pectic substances, one of the cell wall polysaccharides, exist widespread in vegetables and fruits. A surge of recent research has revealed that pectic substances can inhibit gut inflammation and relieve inflammatory bowel disease symptoms. However, physiological functions of pectins are strongly structure dependent. Pectic substances are essentially heteropolysaccharides composed of homogalacturonan and rhamnogalacturonan backbones substituted by various neutral sugar sidechains. Subtle changes in the architecture of pectic substances may remarkably influence the nutritional function of gut microbiota and the host homeostasis of immune system. In this context, developing a structure–function understanding of how pectic substances have an impact on an inflammatory bowel is of primary importance for diet therapy and new drugs. Therefore, the present review has summarized the polycomponent nature of pectic substances, the activities of different pectic polymers, the effects of molecular characteristics and the underlying mechanisms of pectic substances. The immunomodulated property of pectic substances depends on not only the chemical composition but also the physical structure characteristics, such as molecular weight (Mw) and chain conformation. The potential mechanisms by which pectic substances exert their protective effects are mainly reversing the disordered gut microbiota, regulating immune cells, enhancing barrier function, and inhibiting pathogen adhesion. The manipulation of pectic substances on gut health is sophisticated, and the link between structural specificity of pectins and selective regulation needs further exploration. [ABSTRACT FROM AUTHOR]

In recent years, phase separation has been increasingly reported to play a pivotal role in a wide range of biological processes. Due to the close relationships between cancer and disorders in intracellular physiological function, the identification of new mechanisms involved in intracellular regulation has been regarded as a new direction for cancer therapy. Introducing the concept of phase separation into complex descriptions of disease mechanisms may provide many different insights. Here, we review the recent findings on the phase separation of cancer-related proteins, describing the possible relationships between phase separation and key proteins associated with cancer and indicate possible regulatory modalities, especially drug candidates for phase separation, which may provide more effective strategies for cancer therapy. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) has emerged as one of the most prevalent life‐threatening cancers, and the high mortality rate is largely due to the metastasis. The sustained activation of Smad4 and transforming growth factor‐β (TGF‐β) is closely associated with advanced HCC metastasis. However, the regulatory mechanism underlying the aberrant activation of Smad4 and TGF‐β pathway remains elusive. In this study, using a functional screen of USPs siRNA library, we identified ubiquitin‐specific proteases USP10 as a deubiquitinating enzyme (DUB) that sustains the protein level of Smad4 and activates TGF‐β signaling. Further analysis showed that USP10 directly interacts with Smad4 and stabilizes it through the cleavage of its proteolytic ubiquitination, thus promoting HCC metastasis. The suppression of USP10 by either shRNAs or catalytic inhibitor Spautin‐1 significantly inhibited the migration of HCC cells, whereas the reconstitution of Smad4 was able to efficiently rescue this defect. Overall, our study not only uncovers the regulatory effect of USP10 on the protein abundance of Smad4, but also indicates that USP10 could be regarded as a potential intervention target for the metastatic HCC in Smad4‐positive patients. [ABSTRACT FROM AUTHOR]

Stress granules (SGs) are primarily composed of mRNAs that stall at translation initiation and usually appear in the cytoplasm under unusual physiological or pathological conditions such as hypoxia, oxidative stress, and viral infection. Recent studies have indicated that several components of SGs participate in tumourigenesis and cancer metastasis through tumour-associated signalling pathways as well as other mechanisms. Furthermore, some chemotherapy drugs have been reported to induce SGs. Thus, the roles of SGs in cancer treatment have attracted considerable interest. Importantly, disturbing the recruitment of SGs components or microtubule polymerization, as well as other strategies that can abolish SGs formation, is reported to inhibit tumour progression, suggesting that targeting SGs could be a promising strategy for cancer treatment. In this review, we summarize the relationship between SGs and cancer, as well as recent advances in targeting SGs, in the interest of providing new opportunities for cancer treatment. [ABSTRACT FROM AUTHOR]

Retinoids, vitamin A and its natural and synthetic analogues have various functions, including being involved in cell proliferation and differentiation and participating in the formation of vertebrate morphology. In addition, they may activate certain tumour suppressor genes that then act as tumour inhibitors. In the past decades, retinoids have been regarded as promising chemotherapeutic and chemopreventive agents; however, their mechanisms are still not fully understood. Immune cells that participate in or are associated with the immune response play vital roles in the initiation and development of many cancers. Interestingly, recent studies have demonstrated that retinoids can also exert various effects on immune cells including macrophages, T cells and dendritic cells in tumour tissues to execute anti-tumour actions, providing new insights into chemoprevention and chemotherapeutics. In this review, we focus on the effects of retinoids on immune cells in the tumour, which may provide new approaches for antineoplastic strategies. [ABSTRACT FROM AUTHOR]

Summary: With the use of multikinase inhibitors (MKIs) having emerged in recent years, skin toxicities such as hand–foot skin reaction (HFSR) are primary side effects, and they lack effective prediction methods. Here, we updated a previous systematic review by establishing a meta‐analysis of the risk of developing HFSR among patients receiving MKIs and antivascular endothelial growth factor antibody. Publications from PubMed and abstracts presented at the American Society of Clinical Oncology Annual Meeting up to February 5, 2015, were searched to identify relevant studies, and a total of 236 patients with metastatic tumours in nine trials were included for analysis. In the meta‐analysis, the pooled incidence rates of all‐grade and high‐grade HFSR among patients who received the combination therapy were 56.9% [95% confidence interval (CI), 45%‐71.1%] and 14.3% (95% CI, 9%‐24.2%), respectively, with significant differences observed with MKI monotherapy (P < .05). Further subgroup analysis demonstrated that increasing the dosages of bevacizumab (77.8% vs 51.1%, P = .04) and MKIs (64.3% vs 52.6%, P = .02) significantly increased HFSR incidence. Moreover, combination with chemotherapy exerted a minimal effect on HFSR risk (61% vs 55.3%, P = .5). This updated review and meta‐analysis confirm the increased risk of HFSR incidence due to the use of MKIs and antivascular endothelial growth factor antibody. Thus, using these therapies requires safety standards. [ABSTRACT FROM AUTHOR]

Osteosarcoma is the most common bone cancer, and chemotherapy is currently indispensable for its treatment. Adriamycin has been claimed to be the most effective agent for osteosarcoma, however, the outcome of adriamycin chemotherapy remains unsatisfactory. Here, we reported a potent combination therapy that bortezomib, a proteasome inhibitor, enhances adriamycin-induced apoptosis to eliminate osteosarcoma cells and we revealed that the activation of p-eIF2α/ATF4/CHOP axis is the underlying associated mechanisms. First, we observed that bortezomib enhances adriamycin-mediated inhibition of cell proliferation and enhances the apoptosis in osteosarcoma cell lines. Moreover, this drug combination produced more potent tumor-growth inhibitory effects in human osteosarcoma cell line KHOS/NP xenografts. Our study showed that reactive oxygen species (ROS) plays an important role in apoptosis induced by adriamycin plus bortezomib, whereas ROS scavenger NAC could almost completely block the apoptosis induced by the combination treatment. Meanwhile, p-eIF2α is remarkably elevated in the combination group. As a result, ATF4 exhibits strong activation which consequently induces the activation of CHOP and leads to the cell death. Finally, 13 primary osteosarcoma cells demonstrated potent response to the combination treatment. In a human osteosarcoma patient-derived xenograft (PDX) model, our finding suggests that when combined with bortezomib, a relatively low dose of adriamycin produced more potent tumor-growth inhibitory effects without increased toxicity. Thus, our findings not only provide a promising combination strategy to overcome osteosarcoma but also shed new light on the strategy of combining increased ROS and inhibited proteasome to open up new opportunities for the clinical development of chemotherapy regimens. [ABSTRACT FROM AUTHOR]

Neutrophils generated by granulocyte colony-stimulating factor ( GCSF) are functionally immature and, consequently, cannot effectively reduce infection and infection-related mortality in cancer chemotherapy-induced neutropenia ( CCIN). Am80, a retinoic acid ( RA) agonist that enhances granulocytic differentiation by selectively activating transcription factor RA receptor alpha ( RARα), alternatively promotes RA-target gene expression. We found that in normal and malignant primary human hematopoietic specimens, Am80- GCSF combination coordinated proliferation with differentiation to develop complement receptor-3 ( CR3)-dependent neutrophil innate immunity, through altering transcription of RA-target genes RARβ 2, C/ EBPε, CD66, CD11b, and CD18. This led to generation of functional neutrophils capable of fighting infection, whereas neutralizing neutrophil innate immunity with anti- CD18 antibody abolished neutrophil bactericidal activities induced by Am80- GCSF. Further, Am80- GCSF synergy was evaluated using six different dose-schedule-infection mouse CCIN models. The data demonstrated that during 'emergency' granulopoiesis in CCIN mice undergoing transient systemic intravenous bacterial infection, Am80 effect on differentiating granulocytic precursors synergized with GCSF-dependent myeloid expansion, resulting in large amounts of functional neutrophils that reduced infection. Importantly, extensive survival tests covering a full cycle of mouse CCIN with perpetual systemic intravenous bacterial infection proved that without causing myeloid overexpansion, Am80- GCSF generated sufficient numbers of functional neutrophils that significantly reduced infection-related mortality in CCIN mice. These findings reveal a differential mechanism for generating functional neutrophils to reduce CCIN-associated infection and mortality, providing a rationale for future therapeutic approaches. [ABSTRACT FROM AUTHOR]

Suberoylanilide hydroxamic acid (SAHA) is a promising histone deacetylase (HDAC) inhibitor approved by the US Food and Drug Administration (FDA) and whose clinical application for solid tumours is partially limited by decreased susceptibility in cancer cells due to nuclear factor (NF)-κB activation. As an NF-κB inhibitor, celastrol exhibits potent anticancer effects but has failed to enter clinical trials due to its toxicity. In this report, we demonstrated that the combination of celastrol and SAHA exerted substantial synergistic efficacy against human cancer cells in vitro and in vivo accompanied by enhanced caspase-mediated apoptosis. This drug combination inhibited the activation of NF-κB caused by SAHA monotherapy and consequently led to increased apoptosis in cancer cells. Interestingly, E-cadherin was dramatically downregulated in celastrol-resistant cancer cells, and E-cadherin expression was closely related to decreased sensitivity to celastrol. However, our combination treatment significantly augmented the expression of E-cadherin, suggesting that mutual mechanisms contributed to the synergistic anticancer activity. Furthermore, the enhanced anticancer efficacy of celastrol combined with SAHA was validated in a human lung cancer 95-D xenograft model without increased toxicity. Taken together, our data demonstrated the synergistic anticancer effects of celastrol and SAHA due to their reciprocal sensitisation, which was simultaneously regulated by NF-κB and E-cadherin; thus, the combination of celastrol and SAHA was superior to other combination regimens that rely on a single mechanism. Our findings not only open new opportunities for the clinical development of SAHA but should also motivate the clinical investigation of celastrol, which has been hampered by its toxicity. [ABSTRACT FROM AUTHOR]

Small ubiquitin-related modifier-1 ( SUMO-1) modification has been implicated in many important cellular processes, including cell cycle progression, apoptosis, cellular proliferation, and development, but its role in all- trans-retinoic acid ( ATRA)-induced differentiation processes of cancer cells remains unclear. Here, we report for the first time that ATRA-induced differentiation of leukemia and osteosarcoma is accompanied by a decrease in the level of SUMO-1 protein. Our results also demonstrated that depletion or inhibition of SUMO-1 blocks ATRA-induced differentiation, suggesting that SUMO-1 is critical for the differentiation effect of ATRA. Further studies indicated that SUMO-1-promoted ATRA-induced differentiation might be associated with the stabilization of retinoic acid receptor α ( RARα), protecting it from degradation. Moreover, our results suggested that Lys399 is a major site for SUMO-1 conjugation of RARα. We also found that RARα enhanced the transcription of its target genes, which might also contribute to the enhanced differentiating effects of ATRA; however, mutation of Lys399 of RARα inhibits the extents of both SUMO-1 modification and ATRA-induced differentiation. Together, these results indicate that SUMO-1 modification of RARα is a potent mechanism for balancing proliferation and differentiation by controlling the stability of RARα in cancer cells. SUMO-1 modification may thus serve an important role in controlling ATRA-induced cell differentiation in cancers. Structured digital abstract with by (, , ), with by (), and by () [ABSTRACT FROM AUTHOR]