bims-stacyt 2022-03-20 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2022–03–20
eight papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

Improving Cancer Immunotherapy: Exploring and Targeting Metabolism in Hypoxia Microenvironment.
Cancer-associated adipocytes promote the invasion and metastasis in breast cancer through LIF/CXCLs positive feedback loop.
Deletion of Gdf15 reduces ER stress-induced beta cell apoptosis and diabetes.
Inhibition of PRMT5 attenuates cerebral ischemia/reperfusion-Induced inflammation and pyroptosis through suppression of NF-κB/NLRP3 axis.
Emerging Role of High Glucose Levels in Cancer Progression and Therapy.
Attenuating adaptive VEGF-A and IL-8 signaling restores durable tumor control in AR-antagonist-treated prostate cancers.
Role of ER stress inhibitors in the management of diabetes.
Hyperglycemia-triggered ATF6-CHOP pathway aggravates acute inflammatory liver injury by β-catenin signaling.

Front Immunol. 2022 ;13 845923

Improving Cancer Immunotherapy: Exploring and Targeting Metabolism in Hypoxia Microenvironment.

Jinfen Wei, Meiling Hu, Hongli Du.

  Although immunotherapy has achieved good results in various cancer types, a large proportion of patients are limited from the benefits. Hypoxia and metabolic reprogramming are the common and critical factors that impact immunotherapy response. Here, we present current research on the metabolism reprogramming induced by hypoxia on antitumor immunity and discuss the recent progression among preclinical and clinical trials exploring the therapeutic effects combining targeting hypoxia and metabolism with immunotherapy. By evaluating the little clinical translation of the combined therapy, we provide insight into "understanding and regulating cellular metabolic plasticity under the current tumor microenvironment (TME)," which is essential to explore the strategy for boosting immune responses by targeting the metabolism of tumor cells leading to harsh TMEs. Therefore, we highlight the potential value of advanced single-cell technology in revealing the metabolic heterogeneity and corresponding phenotype of each cell subtype in the current hypoxic lesion from the clinical patients, which can uncover potential metabolic targets and therapeutic windows to enhance immunotherapy.

Keywords:  cancer immunotherapy; cell subtypes; hypoxia; metabolic reprogramming; single-cell analysis

DOI:  https://doi.org/10.3389/fimmu.2022.845923
Int J Biol Sci. 2022 ;18(4): 1363-1380

Cancer-associated adipocytes promote the invasion and metastasis in breast cancer through LIF/CXCLs positive feedback loop.

Chong Zhou, Xi He, Chang Tong, Honghui Li, Caifeng Xie, Yudong Wu, Lieliang Wang, Xiaohua Yan, Daya Luo, Yunpeng Tang, Zhongman Cheng, Xiangyang Xiong.

  Cancer-associated adipocytes (CAAs), which are adipocytes transformed by cancer cells, are of great importance in promoting the progression of breast cancer. However, the underlying mechanisms involved in the crosstalk between cancer cells and adipocytes are still unknown. Here we report that CAAs and breast cancer cells communicate with each other by secreting the cytokines leukemia inhibitory factor (LIF) and C-X-C subfamily chemokines (CXCLs), respectively. LIF is a pro-inflammatory cytokine secreted by CAAs, which promotes migration and invasion of breast cancer cells via the Stat3 signaling pathway. The activation of Stat3 induced the secretion of glutamic acid-leucine-arginine (ELR) motif CXCLs (CXCL1, CXCL2, CXCL3 and CXCL8) in tumor cells. Interestingly, CXCLs in turn activated the ERK1/2/NF-κB/Stat3 signaling cascade to promote the expression of LIF in CAAs. In clinical breast cancer pathology samples, the up-regulation of LIF in paracancerous adipose tissue was positively correlated with the activation of Stat3 in breast cancer. Furthermore, we verified that adipocytes enhanced lung metastasis of breast cancer cells, and the combination of EC330 (targeting LIF) and SB225002 (targeting C-X-C motility chemokine receptor 2 (CXCR2)) significantly reduced lung metastasis of breast cancer cells in vivo. Our findings reveal that the interaction of adipocytes with breast cancer cells depends on a positive feedback loop between the cytokines LIF and CXCLs, which promotes breast cancer invasion and metastasis.

Keywords:  ELR+CXC Chemokines; breast cancer; cancer-associated adipocyte; invasion and metastasis; leukemia inhibitory factor

DOI:  https://doi.org/10.7150/ijbs.65227
Endocrinology. 2022 Mar 15. pii: bqac030. [Epub ahead of print]

Deletion of Gdf15 reduces ER stress-induced beta cell apoptosis and diabetes.

Guanlan Xu, Junqin Chen, Seong Ho Jo, Truman B Grayson, Sasanka Ramanadham, Akio Koizumi, Emily L Germain-Lee, Se-Jin Lee, Anath Shalev.

  Endoplasmic reticulum (ER) stress contributes to pancreatic beta cell apoptosis in diabetes, but the factors involved are still not fully elucidated. Growth differentiation factor 15 (GDF15) is a stress response gene and has been reported to be increased and play an important role in various diseases. However, the role of GDF15 in beta cells in the context of ER stress and diabetes is still unclear. In this study, we have discovered that GDF15 promotes ER stress-induced beta cell apoptosis and that downregulation of GDF15 has beneficial effects on beta cell survival in diabetes. Specifically, we found that GDF15 is induced by ER stress in beta cells and human islets, and that the transcription factor C/EBPβ is involved in this process. Interestingly, ER stress-induced apoptosis was significantly reduced in INS-1 cells with Gdf15 knockdown and in isolated Gdf15 knockout mouse islets. In vivo, we found that Gdf15 deletion attenuates streptozotocin-induced diabetes by preserving beta cells and insulin levels. Moreover, deletion of Gdf15 significantly delayed diabetes development in spontaneous ER stress-prone Akita mice. Thus, our findings suggest that GDF15 contributes to ER stress-induced beta cell apoptosis and that inhibition of GDF15 may represent a novel strategy to promote beta cell survival and treat diabetes.

Keywords:  Beta cells; Diabetes; ER stress; apoptosis and GDF15

DOI:  https://doi.org/10.1210/endocr/bqac030
Neurosci Lett. 2022 Mar 09. pii: S0304-3940(22)00133-1. [Epub ahead of print]776 136576

Inhibition of PRMT5 attenuates cerebral ischemia/reperfusion-Induced inflammation and pyroptosis through suppression of NF-κB/NLRP3 axis.

Xiang Wu, Bo Wang, Jiaxi Li, Zhongbo Yang, Yunfei Zhou, Xudong Ma, Zhiyan Kou, Liangchao Jiang, Jinning Song.

  Protein methylation is a prevalent post-translational modification after cerebral ischemia. Protein arginine methyltransferase 5 (PRMT5) is a type of methyltransferase enzyme that can catalyse the formation of methylated residues on histones and non-histone proteins. Accumulating evidence suggested that PRMT5 might play a carcinogenic role in various cancers. However, the role of PRMT5 in cerebral ischaemia/reperfusion (I/R) injury remains unclear. In this project, middle cerebral artery occlusion/reperfusion (MCAO/R) model in mice and oxygen-glucose deprivation/reoxygenation (OGD/R) model in human neuroblastoma SH-SY5Y cells were utilized to mimic disease state of cerebral I/R. We found that expression of inflammatory-related factors [Interleukin (IL)-1β and IL-6)] and pyroptotic-related factor [N-term cleaved Gasdermin-D (GSDMD-N)] were up-regulated in both MCAO/R mice and OGD/R SH-SY5Y cells. In addition, both in vivo and in vitro, PRMT5 was aberrantly upregulated during cerebral I/R. However, these alterations induced by I/R were blocked by PRMT5 inhibitor LLY-283, and enhanced by overexpression of PRMT5. Furthermore, rescue experiment proved that PRMT5 plays a pro-inflammatory and pro-pyroptotic role by activating nuclear factor kappa B (NF-κB)/nucleotide-binding oligomerization domainlike receptor pyrin domain containing 3 (NLRP3) axis. Finally, we observed that treatment of LLY-283 alleviated neurological deficits and reduced infarct volume in the MCAO/R mice. Taken together, PRMT5 may be a potential therapeutic target for cerebral I/R injury.

Keywords:  Cerebral I/R; Inflammation; NF-κB; NLRP3; PRMT5; Pyroptosis

DOI:  https://doi.org/10.1016/j.neulet.2022.136576
Chin J Dent Res. 2022 Mar 16. 25(1): 11-20

Emerging Role of High Glucose Levels in Cancer Progression and Therapy.

Xin Jia Cai, Jian Yun Zhang, Ao Bo Zhang, Xuan Zhou, He Yu Zhang, Tie Jun Li.

  Extensive research has indicated that high glucose levels play an important role in cancer. A high glycaemic index, glycaemic load diet, high sugar intake, high blood glucose and diabetes mellitus all increase the risk of cancer. Various signals are involved in high glucose-induced tumorigenesis, cancer proliferation, apoptosis, invasion and multidrug resistance. Reactive oxygen species might be important targets in cancer progression that are induced by high glucose levels. Drugs such as metformin and resveratrol may inhibit high glucose-induced cancer. As the impact of high glucose levels on cancer progression and therapy is a novel finding, further research is required.

Keywords:  cancer; high glucose; progression; therapy; tumorigenesis

DOI:  https://doi.org/10.3290/j.cjdr.b2752695
Mol Cancer Res. 2022 Mar 18. pii: molcanres.0780.2021. [Epub ahead of print]

Attenuating adaptive VEGF-A and IL-8 signaling restores durable tumor control in AR-antagonist-treated prostate cancers.

Pamela J Maxwell, Melanie McKechnie, Christopher W Armstrong, Judith M Manley, Chee Wee Ong, Jenny Worthington, Ian G Mills, Daniel B Longley, James P Quigley, Amina Zoubedi, Johann S de Bono, Elena Deryugina, Melissa J LaBonte, David J J Waugh.

Inhibiting androgen-signaling using androgen signaling inhibitors (ASI) remains the primary treatment for castrate-resistant prostate cancer. Acquired resistance to androgen receptor (AR)-targeted therapy represents a major impediment to durable clinical response. Understanding resistance mechanisms, including the role of AR expressed in other cell types within the tumour microenvironment, will extend the clinical benefit of AR-targeted therapy. Here we show the ASI Enzalutamide induces vascular catastrophe and promotes hypoxia and microenvironment adaptation. We characterize treatment-induced hypoxia, and subsequent induction of angiogenesis, as novel mechanisms of relapse to Enzalutamide, highlighting the importance of two hypoxia-regulated cytokines in underpinning relapse. We confirmed AR-expression in CD34+ vascular endothelium of biopsy tissue and human vascular endothelial cells (HVEC). Enzalutamide attenuated angiogenic tubule formation and induced cytotoxicity in HVEC in vitro, and rapidly induced sustained hypoxia in LNCaP xenografts. Subsequent reoxygenation, following prolonged Enzalutamide treatment, was associated with increased tumor vessel density and accelerated tumor growth. Hypoxia increased AR expression and transcriptional activity in prostate cells in vitro. Co-inhibition of IL-8 and VEGF-A restored tumor-response in the presence of Enzalutamide, confirming the functional importance of their elevated expression in Enzalutamide-resistant (EnzR)-models. Moreover, co-inhibition of IL-8 and VEGF-A resulted in a durable, effective resolution of Enzalutamide-sensitive prostate tumors. We conclude that concurrent inhibition of two hypoxia induced factors, IL-8 and VEGF-A, prolongs tumor sensitivity to Enzalutamide in pre-clinical models and may delay the onset of Enzalutamide-resistance. Implications: Targeting hypoxia induced signaling may extend the therapeutic benefit of Enzalutamide, providing an improved treatment strategy for patients with resistant disease.

DOI: https://doi.org/10.1158/1541-7786.MCR-21-0780
Eur J Pharmacol. 2022 Mar 12. pii: S0014-2999(22)00154-6. [Epub ahead of print] 174893

Role of ER stress inhibitors in the management of diabetes.

Krishna Prasad M, Sundhar Mohandas, Kunka Mohanram Ramkumar.

  Endoplasmic Reticulum (ER) stress has been established to play a key pathophysiological role in developing metabolic diseases such as Diabetes Mellitus (DM). The complications of DM have been closely associated with deregulation of the unfolded protein response (UPR) signaling pathways, which are critically responsible for restoring homeostasis following ER stress. Chronic ER stress in the background of persistent hyperglycemia, as observed in DM, overwhelms the UPR signaling and commits the cells to apoptosis. The factors such as hyperglycemia, increased reactive oxygen species (ROS), disrupted calcium homeostasis, and overt inflammation serves as major UPR signal transduction pathways, including PKR like ER kinase (PERK), Activating transcription factor 6α/β (ATF6), and Inositol requiring enzyme1α/β (IRE1). The constantly developing understanding of these ER stress mediators has also unraveled their potential as therapeutic targets of small molecules termed ER stress inhibitors. A wide range of both naturally occurring and synthetic compounds have been screened and studied for their properties to inhibit ER stress in various experimental models. This review article elucidates the critical signaling pathways associated with response to ER stress. We shed light on the crosstalk between ER stress mediators with oxidative and inflammatory stress mediators in the background of DM. We extensively summarize the pieces of evidence sourced from preclinical and clinical research about the role of ER stress inhibitors and their pharmacological mechanism of action in alleviating ER stress in diabetes.

Keywords:  Chaperones; Diabetes mellitus; ER stress Inhibitors; Endoplasmic reticulum stress; Therapeutic target; UPR

DOI:  https://doi.org/10.1016/j.ejphar.2022.174893
Cell Death Discov. 2022 Mar 14. 8(1): 115

Hyperglycemia-triggered ATF6-CHOP pathway aggravates acute inflammatory liver injury by β-catenin signaling.

Chao Yang, Zeng Wang, Yuanchang Hu, Shikun Yang, Feng Cheng, Jianhua Rao, Xuehao Wang.

Although hyperglycemia has been documented as an unfavorable element that can further induce liver ischemia-reperfusion injury (IRI), the related molecular mechanisms remain to be clearly elaborated. This study investigated the effective manner of endoplasmic reticulum (ER) stress signaling in hyperglycemia-exacerbated liver IRI. Here we demonstrated that in the liver tissues and Kupffer cells (KCs) of DM patients and STZ-induced hyperglycemic mice, the ER stress-ATF6-CHOP signaling pathway is activated. TLR4-mediated pro-inflammatory activation was greatly attenuated by the addition of 4-phenylbutyrate (PBA), one common ER stress inhibitor. The liver IRI in hyperglycemic mice was also significantly reduced after PBA treatment. In addition, deficiency of CHOP (CHOP-/-) obviously alleviates the hepatic IRI, and pro-inflammatory effects deteriorated by hyperglycemia. In hyperglycemic mice, β-catenin expression was suppressed while the ATF6-CHOP signal was activated. In the liver tissues of PBA-treated or CHOP-/- hyperglycemic mice, the expression of β-catenin was restored. Furthermore, CHOP deficiency can induce protection against hyperglycemia-related liver IRI, which was disrupted by the knockdown of β-catenin will cause this protection to disappear. High glucose (HG) treatment stimulated ATF6-CHOP signaling, reduced cellular β-catenin accumulation, and promoted the TLR4-related inflammation of BMDMs. But the above effects were partially rescued in BMDMs with CHOP deficiency or by PBA treatment. In BMDMs cultured in HG conditions, the anti-inflammatory functions of CHOP-/- were destroyed by the knockdown of β-catenin. Finally, chimeric mice carrying WT or CHOP-/- BMDMs by bone marrow transplantation were adopted to verify the above conclusion. The current study suggested that hyperglycemia could trigger ER stress-ATF6-CHOP axis, inhibit β-catenin activation, accelerate inflammation, and deteriorate liver IRI, thus providing the treatment potential for management of sterile liver inflammation in DM patients.

DOI: https://doi.org/10.1038/s41420-022-00910-z