bims-stacyt 2023-07-30 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2023–07–30
ten papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

Molecular basis of GDF15 induction and suppression by drugs in cardiomyocytes and cancer cells toward precision medicine.
Nitric oxide-induced ribosome collision activates ribosomal surveillance mechanisms.
ER stress activates TAp73α to promote colon cancer cell apoptosis via the PERK-ATF4 pathway.
Tumor aerobic glycolysis confers immune evasion through modulating sensitivity to T cell-mediated bystander killing via TNF-α.
Fructose promotes angiogenesis by improving vascular endothelial cell function and upregulating VEGF expression in cancer cells.
Metabolic stress-induced reciprocal loop of long noncoding RNA ZFAS1 and ZEB1 promotes epithelial-mesenchymal transition and metastasis of pancreatic cancer cells.
Role of Interleukin(IL)-6 in NK Activity to Hypoxic-Induced Highly Invasive Hepatocellular Carcinoma(HCC) Cells.
Tumor-intrinsic LKB1-LIF signaling axis establishes a myeloid niche to promote immune evasion and tumor growth.
ER Stress, the Unfolded Protein Response and Osteoclastogenesis: A Review.
Design and Synthesis of AMPK Activators and GDF15 Inducers.

Sci Rep. 2023 07 26. 13(1): 12061

Molecular basis of GDF15 induction and suppression by drugs in cardiomyocytes and cancer cells toward precision medicine.

Lisa-Maria Winter, Diana Reinhardt, Ariane Schatter, Vivien Tissen, Heike Wiora, Daniel Gerlach, Ulrike Tontsch-Grunt, Florian Colbatzky, Birgit Stierstorfer, Seong-Wook Yun.

GDF15 has recently emerged as a key driver of the development of various disease conditions including cancer cachexia. Not only the tumor itself but also adverse effects of chemotherapy have been reported to contribute to increased GDF15. Although regulation of GDF15 transcription by BET domain has recently been reported, the molecular mechanisms of GDF15 gene regulation by drugs are still unknown, leaving uncertainty about the safe and effective therapeutic strategies targeting GDF15. We screened various cardiotoxic drugs and BET inhibitors for their effects on GDF15 regulation in human cardiomyocytes and cancer cell lines and analyzed in-house and public gene signature databases. We found that DNA damaging drugs induce GDF15 in cardiomyocytes more strongly than drugs with other modes of action. In cancer cells, GDF15 induction varied depending on drug- and cell type-specific gene signatures including mutations in PI3KCA, TP53, BRAF and MUC16. GDF15 suppression by BET inhibition is particularly effective in cancer cells with low activity of the PI3K/Akt axis and high extracellular concentrations of pantothenate. Our findings provide insights that the risk for GDF15 overexpression and concomitant cachexia can be reduced by a personalized selection of anticancer drugs and patients for precision medicine.

DOI: https://doi.org/10.1038/s41598-023-38450-w
Cell Death Dis. 2023 07 26. 14(7): 467

Nitric oxide-induced ribosome collision activates ribosomal surveillance mechanisms.

Laura Ryder, Frederic Schrøder Arendrup, José Francisco Martínez, Goda Snieckute, Chiara Pecorari, Riyaz Ahmad Shah, Anders H Lund, Melanie Blasius, Simon Bekker-Jensen.

Impairment of protein translation can cause stalling and collision of ribosomes and is a signal for the activation of ribosomal surveillance and rescue pathways. Despite clear evidence that ribosome collision occurs stochastically at a cellular and organismal level, physiologically relevant sources of such aberrations are poorly understood. Here we show that a burst of the cellular signaling molecule nitric oxide (NO) reduces translational activity and causes ribosome collision in human cell lines. This is accompanied by activation of the ribotoxic stress response, resulting in ZAKα-mediated activation of p38 and JNK kinases. In addition, NO production is associated with ZNF598-mediated ubiquitination of the ribosomal protein RPS10 and GCN2-mediated activation of the integrated stress response, which are well-described responses to the collision of ribosomes. In sum, our work implicates a novel role of NO as an inducer of ribosome collision and activation of ribosomal surveillance mechanisms in human cells.

DOI: https://doi.org/10.1038/s41419-023-05997-5
J Cancer. 2023 ;14(11): 1946-1955

ER stress activates TAp73α to promote colon cancer cell apoptosis via the PERK-ATF4 pathway.

Shengnan Sun, Yong Yi, Zhi-Xiong Jim Xiao, Hu Chen.

  Colorectal cancer (CRC) is the fourth most diagnosed cancer worldwide. 43% of CRCs harbor p53 mutations. The tumor suppressor p53 induces cell growth arrest and/or apoptosis in response to stress, including endoplasmic reticulum (ER) stress. It has been documented that the p53 gene is mutated in more than 50% of human tumors and loses its tumor suppressor function, suggesting that ER stress-induced apoptosis might not rely on p53. In this study, we found that activation of ER stress promotes p53 null colon cancer cell apoptosis concomitant with an increased level of the TAp73α protein, a homologue of p53 in vitro and in vivo. Knockdown of TAp73α partially restores ER stress-induced apoptosis, indicating that ER stress stimulates apoptosis in a manner dependent on TAp73α, but not p53. Furthermore, we found that ER stress activates TAp73α mRNA and protein expression through PERK signalling, a branch of the unfolded protein response (UPR). Moreover, PERK promotes TAp73α expression by upregulating the expression of the transcription factor ATF4. ATF4 directly activates the transcription of TAp73α. Consistent with this finding, ATF4 knockdown inhibited PERK- or ER stress-induced TAp73α expression. Our findings reveal that ER stress activates TAp73α to promote colon cancer cell apoptosis via the PERK-ATF4 signalling. Therefore, prolonged ER stress or upregulation of TAp73α might be a therapeutic strategy for colon cancer.

Keywords:  ATF4; Cell apoptosis; ER stress; PERK; TAp73α

DOI:  https://doi.org/10.7150/jca.84170
Cell Metab. 2023 Jul 21. pii: S1550-4131(23)00251-6. [Epub ahead of print]

Tumor aerobic glycolysis confers immune evasion through modulating sensitivity to T cell-mediated bystander killing via TNF-α.

Lijian Wu, Yiteng Jin, Xi Zhao, Kaiyang Tang, Yaoning Zhao, Linjie Tong, Xuerong Yu, Ke Xiong, Ce Luo, Jiajun Zhu, Fubing Wang, Zexian Zeng, Deng Pan.

  Metabolic reprogramming toward glycolysis is a hallmark of cancer malignancy. The molecular mechanisms by which the tumor glycolysis pathway promotes immune evasion remain to be elucidated. Here, by performing genome-wide CRISPR screens in murine tumor cells co-cultured with cytotoxic T cells (CTLs), we identified that deficiency of two important glycolysis enzymes, Glut1 (glucose transporter 1) and Gpi1 (glucose-6-phosphate isomerase 1), resulted in enhanced killing of tumor cells by CTLs. Mechanistically, Glut1 inactivation causes metabolic rewiring toward oxidative phosphorylation, which generates an excessive amount of reactive oxygen species (ROS). Accumulated ROS potentiate tumor cell death mediated by tumor necrosis factor alpha (TNF-α) in a caspase-8- and Fadd-dependent manner. Genetic and pharmacological inactivation of Glut1 sensitizes tumors to anti-tumor immunity and synergizes with anti-PD-1 therapy through the TNF-α pathway. The mechanistic interplay between tumor-intrinsic glycolysis and TNF-α-induced killing provides new therapeutic strategies to enhance anti-tumor immunity.

Keywords:  T cell-mediated killing; TNF-α; glycolysis; immune evasion

DOI:  https://doi.org/10.1016/j.cmet.2023.07.001
J Exp Clin Cancer Res. 2023 Jul 28. 42(1): 184

Fructose promotes angiogenesis by improving vascular endothelial cell function and upregulating VEGF expression in cancer cells.

Yanfen Cui, Hui Liu, Zhaosong Wang, He Zhang, Jianfei Tian, Zhiyong Wang, Weijie Song, Hui Guo, Liming Liu, Ruinan Tian, Xiaoyan Zuo, Sixin Ren, Fei Zhang, Ruifang Niu.

   BACKGROUND: Fructose is a very common sugar found in natural foods, while current studies demonstrate that high fructose intake is significantly associated with increased risk of multiple cancers and more aggressive tumor behavior, but the relevant mechanisms are not fully understood.
METHODS: Tumor-grafting experiments and in vitro angiogenesis assays were conducted to detect the effect of fructose and the conditioned medium of fructose-cultured tumor cells on biological function of vascular endothelial cells (VECs) and angiogenesis. 448 colorectal cancer specimens were utilized to analyze the relationship between Glut5 expression levels in VECs and tumor cells and microvascular density (MVD).
RESULTS: We found that fructose can be metabolized by VECs and activate the Akt and Src signaling pathways, thereby enhancing the proliferation, migration, and tube-forming abilities of VECs and thereby promoting angiogenesis. Moreover, fructose can also improve the expression of vascular endothelial growth factor (VEGF) by upregulating the production of reactive oxygen species (ROS) in colorectal cancer cells, thus indirectly enhancing the biological function of VECs. Furthermore, this pro-angiogenic effect of fructose metabolism has also been well validated in clinical colorectal cancer tissues and mouse models. Fructose contributes to angiogenesis in mouse subcutaneous tumor grafts, and MVD is positively correlated with Glut5 expression levels of both endothelial cells and tumor cells of human colorectal cancer specimens.
CONCLUSIONS: These findings establish the direct role and mechanism by which fructose promotes tumor progression through increased angiogenesis, and provide reliable evidence for a better understanding of tumor metabolic reprogramming.

Keywords:  Angiogenesis; Colorectal Cancer; Fructose; VEGF; Vascular Endothelial Cell

DOI:  https://doi.org/10.1186/s13046-023-02765-3
Cancer Sci. 2023 Jul 24.

Metabolic stress-induced reciprocal loop of long noncoding RNA ZFAS1 and ZEB1 promotes epithelial-mesenchymal transition and metastasis of pancreatic cancer cells.

Wenfeng Zhuo, Zhu Zeng, Yuhang Hu, Ping Hu, Shengbo Han, Decai Wang, Fan Wang, Yong Zhao, Yan Huang, Jie Wang, Guozheng Lv, Hongda Wang, Yang Li, Eryang Zhao, Kailin Cai, Gang Zhao.

  Pancreatic cancer (PC) development faces significant metabolic stress due to metabolic reprogramming and a distinct hypovascular nature, often leading to glucose and glutamine depletion. However, the adaption mechanisms by which PC adapts to these metabolic challenges have not yet been completely explored. Here, we found that metabolic stress induced by glucose and glutamine deprivation led to an overexpression of ZNFX1 antisense RNA 1 (ZFAS1). This overexpression played a significant role in instigating PC cell epithelial-mesenchymal transition (EMT) and metastasis. Mechanistically, ZFAS1 enhanced the interaction between AMPK, a key kinase, and ZEB1, the primary regulator of EMT. This interaction resulted in the phosphorylation and subsequent stabilization of ZEB1. Interestingly, ZEB1 also reciprocally influenced the transcription of ZFAS1 by binding to its promoter. Furthermore, when ZFAS1 was depleted, the nutrient deprivation-induced EMT of PC cells and lung metastasis in nude mice were significantly inhibited. Our investigations also revealed that ZFAS1-rich exosomes released from cells suffering glucose and glutamine deprivation promoted the EMT and metastasis of recipient PC cells. Corroborating these findings, a correlated upregulation of ZFAS1 and ZEB1 expression was observed in PC tissues and was associated with a poor overall survival rate for patients. Our findings highlight the involvement of a long noncoding RNA-driven metabolic adaptation in promoting EMT and metastasis of PC, suggesting ZFAS1 as a promising novel therapeutic target for PC metabolic treatment.

Keywords:  EMT; exosome; lncRNA; metabolic stress; metastasis; pancreatic cancer

DOI:  https://doi.org/10.1111/cas.15905
J Microbiol Biotechnol. 2023 Jul 28. 33(7): 864-874

Role of Interleukin(IL)-6 in NK Activity to Hypoxic-Induced Highly Invasive Hepatocellular Carcinoma(HCC) Cells.

Hwan Hee Lee, Hyojung Kang, Hyosun Cho.

  Natural killer (NK) cell dysfunctions against hepatocellular carcinoma (HCC) in a hypoxic environment. Many solid tumors are present in a hypoxic condition, which changes the effector function of various immune cells. The transcription of hypoxic-inducible factors (HIFs) in cancer cells make it possible to adapt to their hypoxic environment and to escape the immune surveillance of NK cells. Recently, the correlation between the transcription of HIF-1α and pro-inflammatory cytokines has been reported. Interleukin (IL)-6 is higher in cancers with a highly invasive ability, and is closely related to the metastasis of cancers. This study showed that the expression of HIF-1α in HCC cells was associated with the presence of IL-6 in the environment of HCC-NK cells. Blocking of IL-6 by antibody in the HCC-NK interaction changed the production of several cytokines including TGF-β, IL-1, IL-18 and IL-21. Interestingly, in a co-culture of HIF-1α-expressed HCC cells and NK cells, blocking of IL-6 increased the production of IL-21 in their supernatants. In addition, the absence of IL-6 significantly enhanced the cytotoxic ability and the expression of the activating receptors (NKG2D, NKp44, and NKG2C) in NK cells to HIF-1α-expressed HCC cells. These effects might be made by the decreased expression of HIF-1α in HCC cells through the inhibited phosphorylation of STAT3. In conclusion, the absence of IL-6 in the interaction of HIF-1α-expressed HCC cells and NK cells could enhance the antitumor activity of NK cells to HCC cells.

Keywords:  HIF-1α; Hepatocellular carcinoma (HCC); Interleukin (IL)-6; Natural killer (NK) cell; hypoxia

DOI:  https://doi.org/10.4014/jmb.2304.04023
bioRxiv. 2023 Jul 17. pii: 2023.07.15.549147. [Epub ahead of print]

Tumor-intrinsic LKB1-LIF signaling axis establishes a myeloid niche to promote immune evasion and tumor growth.

Ali Rashidfarrokhi, Ray Pillai, Yuan Hao, Warren L Wu, Burcu Karadal-Ferrena, Sofia G Dimitriadoy, Michael Cross, Anna H Yeaton, Shih Ming Huang, Arjun J Bhutkar, Alberto Herrera, Sahith Rajalingam, Makiko Hayashi, Kuan-Lin Huang, Eric Bartnicki, Anastasia-Maria Zavitsanou, Corrin A Wohlhieter, Sarah E Leboeuf, Ting Chen, Cynthia Loomis, Valeria Mezzano, Ruth Kulicke, Fred P Davis, Nicolas Stransky, Gromoslaw A Smolen, Charles M Rudin, Andre L Moreira, Kamal M Khanna, Harvey I Pass, Kwok-Kin Wong, Shohei Koide, Aristotelis Tsirigos, Sergei B Koralov, Thales Papagiannakopoulos.

Tumor mutations can influence the surrounding microenvironment leading to suppression of anti-tumor immune responses and thereby contributing to tumor progression and failure of cancer therapies. Here we use genetically engineered lung cancer mouse models and patient samples to dissect how LKB1 mutations accelerate tumor growth by reshaping the immune microenvironment. Comprehensive immune profiling of LKB1 -mutant vs wildtype tumors revealed dramatic changes in myeloid cells, specifically enrichment of Arg1 + interstitial macrophages and SiglecF Hi neutrophils. We discovered a novel mechanism whereby autocrine LIF signaling in Lkb1 -mutant tumors drives tumorigenesis by reprogramming myeloid cells in the immune microenvironment. Inhibiting LIF signaling in Lkb1 -mutant tumors, via gene targeting or with a neutralizing antibody, resulted in a striking reduction in Arg1 + interstitial macrophages and SiglecF Hi neutrophils, expansion of antigen specific T cells, and inhibition of tumor progression. Thus, targeting LIF signaling provides a new therapeutic approach to reverse the immunosuppressive microenvironment of LKB1 -mutant tumors.

DOI: https://doi.org/10.1101/2023.07.15.549147
Biomolecules. 2023 Jun 28. pii: 1050. [Epub ahead of print]13(7):

ER Stress, the Unfolded Protein Response and Osteoclastogenesis: A Review.

Wangli Huang, Yining Gong, Liang Yan.

  Endoplasmic reticulum (ER) stress and its adaptive mechanism, the unfolded protein response (UPR), are triggered by the accumulation of unfolded and misfolded proteins. During osteoclastogenesis, a large number of active proteins are synthesized. When an imbalance in the protein folding process occurs, it causes osteoclasts to trigger the UPR. This close association has led to the role of the UPR in osteoclastogenesis being increasingly explored. In recent years, several studies have reported the role of ER stress and UPR in osteoclastogenesis and bone resorption. Here, we reviewed the relevant literature and discussed the UPR signaling cascade response, osteoclastogenesis-related signaling pathways, and the role of UPR in osteoclastogenesis and bone resorption in detail. It was found that the UPR signal (PERK, CHOP, and IRE1-XBP1) promoted the expression of the receptor activator of the nuclear factor-kappa B ligand (RANKL) in osteoblasts and indirectly enhanced osteoclastogenesis. IRE1 promoted osteoclastogenesis via promoting NF-κB, MAPK signaling, or the release of pro-inflammatory factors (IL-6, IL-1β, and TNFα). CREBH promoted osteoclast differentiation by promoting NFATc1 expression. The PERK signaling pathway also promoted osteoclastogenesis through NF-κB and MAPK signaling pathways, autophagy, and RANKL secretion from osteoblasts. However, salubrinal (an inhibitor of eIF2α dephosphorylation that upregulated p-eIF2α expression) directly inhibited osteoclastogenesis by suppressing NFATc1 expression and indirectly promoted osteoclastogenesis by promoting RANKL secretion from osteoblasts. Therefore, the specific effects and mechanisms of p-PERK and its downstream signaling on osteoclastogenesis still need further experiments to confirm. In addition, the exact role of ATF6 and BiP in osteoclastogenesis also required further exploration. In conclusion, our detailed and systematic review provides some references for the next step to fully elucidate the relationship between UPR and osteoclastogenesis, intending to provide new insights for the treatment of diseases caused by osteoclast over-differentiation, such as osteoporosis.

Keywords:  ER stress; UPR; bone resorption; osteoclastogenesis

DOI:  https://doi.org/10.3390/biom13071050
Molecules. 2023 Jul 17. pii: 5468. [Epub ahead of print]28(14):

Design and Synthesis of AMPK Activators and GDF15 Inducers.

Meijian Zhang, Andrea Bagán, Donna Martínez, Emma Barroso, Xavier Palomer, Santiago Vázquez, Carmen Escolano, Manuel Vázquez-Carrera.

  Targeting growth differentiation factor 15 (GDF15) is a recent strategy for the treatment of obesity and type 2 diabetes mellitus (T2DM). Here, we designed, synthesized, and pharmacologically evaluated in vitro a novel series of AMPK activators to upregulate GDF15 levels. These compounds were structurally based on the (1-dibenzylamino-3-phenoxy)propan-2-ol structure of the orphan ubiquitin E3 ligase subunit protein Fbxo48 inhibitor, BC1618. This molecule showed a better potency than metformin, increasing GDF15 mRNA levels in human Huh-7 hepatic cells. Based on BC1618, structural modifications have been performed to create a collection of diversely substituted new molecules. Of the thirty-five new compounds evaluated, compound 21 showed a higher increase in GDF15 mRNA levels compared with BC1618. Metformin, BC1618, and compound 21 increased phosphorylated AMPK, but only 21 increased GDF15 protein levels. Overall, these findings indicate that 21 has a unique capacity to increase GDF15 protein levels in human hepatic cells compared with metformin and BC1618.

Keywords:  (1-dibenzylamino-3-phenoxy)propan-2-ol; AMPK; BC1618; GDF15

DOI:  https://doi.org/10.3390/molecules28145468