bims-stacyt 2024-10-13 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2024–10–13
fourteen papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

ATF4-dependent and independent mitokine secretion from OPA1 deficient skeletal muscle in mice is sexually dimorphic.
GDF15 enhances anoikis resistance and metastasis of gastric cancer through protective autophagy.
Adipose tissue-derived extracellular vesicles from obese mice suppressed splenocyte-mediated pancreatic cancer cell death.
Tumor-derived IL-6 promotes chordoma invasion by stimulating tumor-associated macrophages M2 polarization and TNFα secretion.
Pancreatic cancer cells overexpressing interleukin 6 induce T-cell-mediated tumor clearance and durable anti-tumor immune response.
USP15 inhibits hypoxia-induced IL-6 signaling by deubiquitinating and stabilizing MeCP2.
O-GlcNAcylation of ATP-citrate lyase couples glucose supply to lipogenesis for rapid tumor cell proliferation.
From starvation to time-restricted eating: a review of fasting physiology.
Lipids in the tumor microenvironment: immune modulation and metastasis.
Mechanisms of neural infiltration-mediated tumor metabolic reprogramming impacting immunotherapy efficacy in non-small cell lung cancer.
The role of extracellular vesicles in cancer.
In vitro models of the crosstalk between multiple myeloma and stromal cells recapitulate the mild NF-κB activation observed in vivo.
Chemical inhibition of the integrated stress response impairs the ubiquitin-proteasome system.
Chemoresistance and the tumor microenvironment: the critical role of cell-cell communication.

Front Endocrinol (Lausanne). 2024 ;15 1325286

ATF4-dependent and independent mitokine secretion from OPA1 deficient skeletal muscle in mice is sexually dimorphic.

Jennifer Streeter, Luis Persaud, Jason Gao, Deeraj Manika, Will Fairman, Luis Miguel García-Peña, Alex Marti, Chethan Manika, Shreya Gaddi, Brandon Schickling, Renata O Pereira, E Dale Abel.

   Introduction: Reducing Optic Atrophy 1 (OPA1) expression in skeletal muscle in male mice induces Activation Transcription Factor 4 (ATF4) and the integrated stress response (ISR). Additionally, skeletal muscle secretion of Fibroblast Growth Factor 21 (FGF21) is increased, which mediates metabolic adaptations including resistance to diet-induced obesity (DIO) and glucose intolerance in these mice. Although FGF21 induction in this model can be reversed with pharmacological attenuation of ER stress, it remains to be determined if ATF4 is responsible for FGF21 induction and its metabolic benefits in this model.
Methods: We generated mice with homozygous floxed Opa1 and Atf4 alleles and a tamoxifen-inducible Cre transgene controlled by the human skeletal actin promoter to enable simultaneous depletion of OPA1 and ATF4 in skeletal muscle (mAO DKO). Mice were fed high fat (HFD) or control diet and evaluated for ISR activation, body mass, fat mass, glucose tolerance, insulin tolerance and circulating concentrations of FGF21 and growth differentiation factor 15 (GDF15).
Results: In mAO DKO mice, ATF4 induction is absent. Other indices of ISR activation, including XBP1s, ATF6, and CHOP were induced in mAO DKO males, but not in mOPA1 or mAO DKO females. Resistance to diet-induced obesity was not reversed in mAO DKO mice of both sexes. Circulating FGF21 and GDF15 illustrated sexually dimorphic patterns. Loss of OPA1 in skeletal muscle increases circulating FGF21 in mOPA1 males, but not in mOPA1 females. Additional loss of ATF4 decreased circulating FGF21 in mAO DKO male mice, but increased circulating FGF21 in female mAO DKO mice. Conversely, circulating GDF15 was increased in mAO DKO males and mOPA1 females, but not in mAO DKO females.
Conclusion: Sex differences exist in the transcriptional outputs of the ISR following OPA deletion in skeletal muscle. Deletion of ATF4 in male and female OPA1 KO mice does not reverse the resistance to DIO. Induction of circulating FGF21 is ATF4 dependent in males, whereas induction of circulating GDF15 is ATF4 dependent in females. Elevated GDF15 in males and FGF21 in females could reflect activation by other transcriptional outputs of the ISR, that maintain mitokine-dependent metabolic protection in an ATF4-independent manner.

Keywords:  FGF21; insulin resistance; integrated stress response; mitochondria; obesity

DOI:  https://doi.org/10.3389/fendo.2024.1325286
Cell Signal. 2024 Oct 08. pii: S0898-6568(24)00430-3. [Epub ahead of print] 111457

GDF15 enhances anoikis resistance and metastasis of gastric cancer through protective autophagy.

Xinyu Gao, Zhongwei Zhang, Qinyi Li, Guokai Tai, ZhiDong Wang.

  Distant metastasis is a prevalent cause of mortality in gastric cancer (GC) patients. Anoikis, a process that induces cell death when cells get detached from the extracellular matrix (ECM), acts as a barrier to tumor metastasis. To survive in the circulatory system and metastasize, tumor cells must acquire anoikis resistance. It is crucial to identify the molecular processes that cause resistance to anoikis in GC since this might lead to the discovery of novel treatment targets and improve the long-term survival of GC patients. In this study, we employed quantitative proteomics to identify growth differentiation factor 15 (GDF15) as a key factor in GC anoikis resistance. We found that GDF15 enhances protective autophagy, thereby promoting anoikis resistance in GC cells. Furthermore, through DNA pull down assay, activating transcription factor 2 (ATF2) was found to be a critical regulator of GDF15 expression, acting as a transcriptional activator of GDF15. Collectively, these discoveries indicate that ATF2 and GDF15 have great potential as target candidates for developing therapeutic strategies to address the metastasis of GC.

Keywords:  ATF2; Anoikis; Autophagy; GDF15; Gastric cancer; Metastasis

DOI:  https://doi.org/10.1016/j.cellsig.2024.111457
Food Nutr Res. 2024 ;68

Adipose tissue-derived extracellular vesicles from obese mice suppressed splenocyte-mediated pancreatic cancer cell death.

Inae Jeong, Shinjung Park, Jinbum Park, Ok-Kyung Kim.

   Background: Obesity is a risk factor for pancreatic cancer and negatively contributes to the immune system. However, the mechanisms by which obesity mediates these actions are still poorly understood. Recent studies have demonstrated that extracellular vesicles (EVs) are key mediators of communication between cells and may influence various aspects of cancer progression.
Objectives: We aim to explore the influence of EVs derived from adipose tissue of obese mice on cytokine production within the interactions between cancer cells and immune cells.
Design: We isolated EVs from the adipose tissue of both C57BL6/J mice and Ob/Ob mice. Subsequently, we treated EVs with Panc02 cells, the murine ductal pancreatic cancer cell line, which were co-cultured with splenocytes. Viability and SMAD4 gene expression were examined in Panc02 cells, and cytokine concentrations of IL-6, IL-4, IL-12, and IL-12p70 were measured in the cultured medium.
Results: Interestingly, we observed a significant reduction in splenocyte-mediated Panc02 cell death when treated with EVs derived from the adipose tissue of Ob/Ob mice, compared to those from C57BL6/J mice. Additionally, EVs from Ob/Ob mice-derived adipose tissue significantly increased the levels of IL-4, IL-2, and IL-12p70 in the culture media of Panc02 cells co-cultured with splenocytes, compared to EVs from C57BL6/J mice-derived adipose tissue.
Conclusion: Adipose tissue-derived EVs from obese mice suppressed splenocyte-mediated Panc02 cell death and upregulated IL-4, IL-2, and IL-12p70 in cultured medium.

Keywords:  adipose tissue; extracellular vesicles; immunity; obesity; pancreatic cancer

DOI:  https://doi.org/10.29219/fnr.v68.10545
Int Immunopharmacol. 2024 Oct 09. pii: S1567-5769(24)01837-X. [Epub ahead of print]143(Pt 1): 113315

Tumor-derived IL-6 promotes chordoma invasion by stimulating tumor-associated macrophages M2 polarization and TNFα secretion.

Yujia Chen, Yuduo Guo, Shenglun Li, Jiacheng Xu, Chao Zhao, Jun Wang, Jingjing Yang, Weihai Ning, Yanming Qu, Mingshan Zhang, Shengdian Wang, Hongwei Zhang.

   AIMS: Chordoma is a rare and aggressive bone tumor with high-recurrence and lack of effective treatment methods. Tumor associated macrophages (TAMs) are abundant in tumor microenvironment (TME) and polarize toward M2 in chordoma. It has been observed that the high proportion of M2 cells is associated with chordoma rapid progression. However, the mechanism of TAMs polarization and promotion to tumor progression in chordoma is still unclear. The is an urgent need for further research.
MATERIALS AND METHODS: Flow cytometry and immunohistochemical staining was used to detect the degree of macrophages infiltration in chordoma. A co-culture model of chordoma cells and macrophages was established in vitro to investigate the effects of their interaction on cell function, cytokine secretion, and RNA transcriptome expression.
KEY FINDINGS: In this study, we found M2 macrophage was predominantly abundant immune cell population in chordoma, and its proportion was associated with the degree of bone destruction. We demonstrated that interleukin 6 (IL-6) derived from chordoma cells could induce TAMs polarization by activating STAT3 phosphorylation, and TAMs could enhance chordoma cells migration and invasion through TNFα/NF-κB pathway. The interaction of chordoma cells and TAMs could promote the bone destruction-related factor Cathepsin B (CTSB) and inhibitory immune checkpoints expression. We also confirmed blocking IL-6/STAT3 pathway could significantly attenuate the M2 polarization of TAMs and decrease the secretion of TNFα.
SIGNIFICANCE: This study illustrates the dynamics between chordoma cells and TAMs in promoting chordoma invasion and suggests that IL-6/STAT3 pathway is a potential therapeutic target to reduce TAM-induced chordoma invasion.

Keywords:  Chordoma; IL-6; STAT3; TNFα; Tumor-associated macrophage

DOI:  https://doi.org/10.1016/j.intimp.2024.113315
bioRxiv. 2024 Sep 27. pii: 2024.09.26.615308. [Epub ahead of print]

Pancreatic cancer cells overexpressing interleukin 6 induce T-cell-mediated tumor clearance and durable anti-tumor immune response.

Paige C Arneson-Wissink, Alexandra Q Bartlett, Heike Mendez, Xinxia Zhu, Jessica Dickie, Matthew McWhorter, Peter R Levasseur, Parham Diba, Katelyn T Byrne, Gregory D Scott, Robert Eil, Aaron J Grossberg.

Tumor immune resistance is recognized as a contributor to low survivorship in pancreatic ductal adenocarcinoma (PDAC). We developed a novel murine model of spontaneous PDAC clearance, generated by overexpressing interleukin-6 (IL-6) in orthotopically implanted PDAC cancer cells (OT-PDAC IL6 ). Circulating IL-6 was 100-fold higher in OT-PDAC IL6 than in OT-PDAC parental mice. OT-PDAC IL6 tumors were present at 5 days post-implantation, and undetectable by 10 days post implantation. Flow cytometry revealed increased T cells and NK cells, and decreased T regulatory cells in OT-PDAC IL6 as compared to OT-PDAC parental tumors. Increased lymphoid aggregates were apparent by histological assessment and may account for elevated T cell content. Antibody-based depletion of CD4 + and CD8 + T cells prevented tumor clearance and significantly reduced survival of OT-PDAC IL6 mice. The anti-tumor immune response to OT-PDAC IL6 rendered mice immune to re-challenge with OT-PDAC parental tumors. In high concentrations, IL-6 acts in opposition to previously described pro-tumorigenic effects by enhancing the T cell-mediated anti-tumor response to PDAC.
Statement of Significance: Interleukin 6 overexpression in pancreatic ductal adenocarcinoma cells induces T cell-driven tumor clearance that is rapid and durable. Supraphysiologic levels of interleukin 6 are sufficient to drive an anti-tumor immune microenvironment hallmarked by increased lymphoid aggregate formation, increased CD4 T cell abundance, and decreased Treg abundance.

DOI: https://doi.org/10.1101/2024.09.26.615308
FEBS J. 2024 Oct 07.

USP15 inhibits hypoxia-induced IL-6 signaling by deubiquitinating and stabilizing MeCP2.

Zi-Tong Zhang, Shu-Xuan Niu, Chen-Hao Yu, Shi-Yuan Wan, Jiao Wang, Cheng-Yu Liu, Ling Zheng, Kun Huang, Yu Zhang.

  Methyl-CpG binding protein 2 (MeCP2) is an important X-linked DNA methylation reader and a key heterochromatin organizer. The expression level of MeCP2 is crucial, as indicated by the observation that loss-of-function mutations of MECP2 cause Rett syndrome, whereas an extra copy spanning the MECP2 locus results in MECP2 duplication syndrome, both being progressive neurodevelopmental disorders. Our previous study demonstrated that MeCP2 protein expression is rapidly induced by renal ischemia-reperfusion injury (IRI) and protects the kidney from IRI through transcriptionally repressing the interleukin-6 (IL-6)/signal transducer and activator of transcription 3 signaling pathway. However, the mechanisms underlying the upregulation of MeCP2 have remained elusive. Here, by using two hypoxia cell models, hypoxia and reoxygenation and cobalt chloride stimulation, we confirmed that the removal of lysine 48-linked ubiquitination from MeCP2 prevented its proteasome-dependent degradation under hypoxic conditions. Through unbiased screening based on a deubiquitinating enzymes library, we identified ubiquitin-specific protease 15 (USP15) as a stabilizer of MeCP2. Further studies revealed that USP15 could attenuate hypoxia-induced MeCP2 degradation by cleaving lysine 48-linked ubiquitin chains from MeCP2, primarily targeting its C-terminal domain. Consistently, USP15 inhibited hypoxia-induced signal transducer and activator of transcription 3 activation, resulting in reduced transcription of IL-6 downstream genes. In summary, our study reveals an important role for USP15 in the maintenance of MeCP2 stability and the regulation of IL-6 signaling.

Keywords:  IL‐6 signaling; MeCP2; USP15; deubiquitination; hypoxia

DOI:  https://doi.org/10.1111/febs.17282
Proc Natl Acad Sci U S A. 2024 Oct 15. 121(42): e2402674121

O-GlcNAcylation of ATP-citrate lyase couples glucose supply to lipogenesis for rapid tumor cell proliferation.

Jia Liu, Yang Wang, Miaomiao Tian, Mingjie Xia, Yi Zheng, Miao Hao, Yuqiang Qian, Hengyao Shu, Wenxia Zhang, Pinghui Peng, Zhexuan Zhao, Kejian Dong, Wanting Peng, Tian Gao, Zhanjun Li, Xin Jin, Min Wei, Yunpeng Feng.

  Elevated lipid synthesis is one of the best-characterized metabolic alterations in cancer and crucial for membrane expansion. As a key rate-limiting enzyme in de novo fatty acid synthesis, ATP-citrate lyase (ACLY) is frequently up-regulated in tumors and regulated by posttranslational modifications (PTMs). Despite emerging evidence showing O-GlcNAcylation on ACLY, its biological function still remains unknown. Here, we observed a significant upregulation of ACLY O-GlcNAcylation in various types of human tumor cells and tissues and identified S979 as a major O-GlcNAcylation site. Importantly, S979 O-GlcNAcylation is required for substrate CoA binding and crucial for ACLY enzymatic activity. Moreover, it is sensitive to glucose fluctuation and decisive for fatty acid synthesis as well as tumor cell proliferation. In response to EGF stimulation, both S979 O-GlcNAcylation and previously characterized S455 phosphorylation played indispensable role in the regulation of ACLY activity and cell proliferation; however, they functioned independently from each other. In vivo, streptozocin treatment- and EGFR overexpression-induced growth of xenograft tumors was mitigated once S979 was mutated. Collectively, this work helps comprehend how cells interrogate the nutrient enrichment for proliferation and suggests that although mammalian cell proliferation is controlled by mitogen signaling, the ancient nutrition-sensing mechanism is conserved and still efficacious in the cells of multicellular organisms.

Keywords:  ATP-citrate lyase; CoA association; O-GlcNAcylation; fatty acid synthesis; tumor cell proliferation

DOI:  https://doi.org/10.1073/pnas.2402674121
Int J Obes (Lond). 2024 Oct 05.

From starvation to time-restricted eating: a review of fasting physiology.

Candida J Rebello, Dachuan Zhang, Joseph C Anderson, Rebecca F Bowman, Pamela M Peeke, Frank L Greenway.

We have long known that subjects with obesity who fast for several weeks survive. Calculations that assume the brain can only use glucose indicated that all carbohydrate and protein sources would be consumed by the brain within several weeks yet subjects with obesity who fasted for several weeks survived. This anomaly led to the determination of the metabolic role of ketone bodies. Subsequent studies transformed our understanding of ketone bodies and illustrated the value of challenging the norm and adapting theory to evidence. Although prolonged fasting is no longer a treatment for obesity, the early studies of starvation provided valuable insights about macronutrient metabolism and ketone body adaptations that fasting elicits. Intermittent fasting and its variants such as time-restricted eating are fasting models that are far less regimented than starvation and severe calorie restriction; yet they produce metabolic benefits. The mechanisms that produce the metabolic changes that intermittent fasting elicits are relatively unknown. In this article, we review the physiology of starvation, starvation adaptation diets, diet-induced ketosis, and intermittent fasting. Understanding the premise and physiology that these regimens induce is necessary to draw parallels and provoke thoughts on the mechanisms underlying the metabolic benefits of intermittent fasting and its variants.

DOI: https://doi.org/10.1038/s41366-024-01641-0
Front Oncol. 2024 ;14 1435480

Lipids in the tumor microenvironment: immune modulation and metastasis.

Gloria Pascual, Salvador Aznar Benitah.

  Tumor cells can undergo metabolic adaptations that support their growth, invasion, and metastasis, such as reprogramming lipid metabolism to meet their energy demands and to promote survival in harsh microenvironmental conditions, including hypoxia and acidification. Metabolic rewiring, and especially alterations in lipid metabolism, not only fuel tumor progression but also influence immune cell behavior within the tumor microenvironment (TME), leading to immunosuppression and immune evasion. These processes, in turn, may contribute to the metastatic spread of cancer. The diverse metabolic profiles of immune cell subsets, driven by the TME and tumor-derived signals, contribute to the complex immune landscape in tumors, affecting immune cell activation, differentiation, and effector functions. Understanding and targeting metabolic heterogeneity among immune cell subsets will be crucial for developing effective cancer immunotherapies that can overcome immune evasion mechanisms and enhance antitumor immunity.

Keywords:  cancer immunotherapy; lipid metabolism; metabolic adaptations; tumor metabolism; tumor micreoenvironment (TME)

DOI:  https://doi.org/10.3389/fonc.2024.1435480
J Exp Clin Cancer Res. 2024 Oct 10. 43(1): 284

Mechanisms of neural infiltration-mediated tumor metabolic reprogramming impacting immunotherapy efficacy in non-small cell lung cancer.

Yuanyuan Zheng, Lifeng Li, Zhibo Shen, Longhao Wang, Xiaoyu Niu, Yujie Wei, Shilong Sun, Jie Zhao.

   BACKGROUND: Current evidence underlines the active role of neural infiltration and axonogenesis within the tumor microenvironment (TME), with implications for tumor progression. Infiltrating nerves stimulate tumor growth and dissemination by secreting neurotransmitters, whereas tumor cells influence nerve growth and differentiation through complex interactions, promoting tumor progression. However, the role of neural infiltration in the progression of non-small cell lung cancer (NSCLC) remains unclear.
METHODS: This study employs the techniques of immunohistochemistry, immunofluorescence, RNA sequencing, molecular biology experiments, and a murine orthotopic lung cancer model to deeply analyze the specific mechanisms behind the differential efficacy of NSCLC immunotherapy from the perspectives of neuro-tumor signal transduction, tumor metabolism, and tumor immunity.
RESULTS: This study demonstrates that nerve growth factor (NGF) drives neural infiltration in NSCLC, and 5-hydroxytryptamine (5-HT), which is secreted by nerves, is significantly elevated in tumors with extensive neural infiltration. Transcriptome sequencing revealed that 5-HT enhanced glycolysis in NSCLC cells. Pathway analysis indicated that 5-HT activated the PI3K/Akt/mTOR pathway, promoting tumor metabolic reprogramming. This reprogramming exacerbated immunosuppression in the TME. Neutralizing 5-HT-mediated metabolic reprogramming in tumor immunity enhanced the efficacy of PD-1 monoclonal antibody treatment in mice.
CONCLUSIONS: The findings of this study provide a novel perspective on the crosstalk between nerves and lung cancer cells and provide insights into further investigations into the role of nerve infiltration in NSCLC progression.

Keywords:  5-hydroxytryptamine; Neural infiltration; Non-small cell lung cancer; Tumor metabolic reprogramming; Tumor microenvironment

DOI:  https://doi.org/10.1186/s13046-024-03202-9
Curr Top Membr. 2024 ;pii: S1063-5823(24)00018-8. [Epub ahead of print]94 247-285

The role of extracellular vesicles in cancer.

Elizabeth Cristina Perez Hurtado, Juan Sebastian Henao Agudelo, Rodrigo Augusto Foganholi da Silva, Thiago Albuquerque Viração, Célio Junior da Costa Fernandes.

  Extracellular vesicles (EVs), which include small EVs such as exosomes, play a critical role in intercellular communication and are produced by both cancer and non-cancer cells. Several studies have shown that cancer cells exploit various strategies to regulate the biogenesis, composition, and functions of EVs primarily to promote cancer progression. Given that exosomes originate from major sorting hubs at the limiting membrane of endosomes, they are central to a signaling network that connects external stimuli with intrinsic tumor cell features. Exosomes contain diverse repertoires of molecular cargos, such as proteins, lipids, and nucleic acids, which determine their heterogeneity and functional properties in cancer progression. Therefore, targeting exosome biogenesis will enhance our understanding of tumorigenesis and also promote the discovery of novel approaches for cancer therapy. In this chapter we summarize the machinery of exosome biogenesis and the local, distant, and systemic effects of exosomes released by cancer cells. Furthermore, we explore how these exosomes regulate the anti-tumor immune response and epigenetic mechanisms to sustain cancer progression and their implications in cancer prevention and treatment.

Keywords:  Cancer progression; Cancer therapy; Cell communication; Epigenetic modifiers; Exosome; Immune surveillance; MicroRNAs; Rabs proteins; Small extracellular vesicles; Tumor microenvironment

DOI:  https://doi.org/10.1016/bs.ctm.2024.06.010
Cell Death Dis. 2024 Oct 06. 15(10): 731

In vitro models of the crosstalk between multiple myeloma and stromal cells recapitulate the mild NF-κB activation observed in vivo.

Federica Colombo, Virginia Guzzeloni, Cise Kizilirmak, Francesca Brambilla, Jose Manuel Garcia-Manteiga, Anna Sofia Tascini, Federica Moalli, Francesca Mercalli, Maurilio Ponzoni, Rosanna Mezzapelle, Marina Ferrarini, Elisabetta Ferrero, Roberta Visone, Marco Rasponi, Marco E Bianchi, Samuel Zambrano, Alessandra Agresti.

Multiple myeloma (MM) is linked to chronic NF-κB activity in myeloma cells, but this activity is generally considered a cell-autonomous property of the cancer cells. The precise extent of NF-κB activation and the contributions of the physical microenvironment and of cell-to-cell communications remain largely unknown. By quantitative immunofluorescence, we found that NF-κB is mildly and heterogeneously activated in a fraction of MM cells in human BMs, while only a minority of MM cells shows a strong activation. To gain quantitative insights on NF-κB activation in living MM cells, we combined advanced live imaging of endogenous p65 Venus-knocked-in in MM.1S and HS-5 cell lines to model MM and mesenchymal stromal cells (MSCs), cell co-cultures, microfluidics and custom microbioreactors to mimic the 3D-interactions within the bone marrow (BM) microenvironment. We found that i) reciprocal MM-MSC paracrine crosstalk and cell-to-scaffold interactions shape the inflammatory response in the BM; ii) the pro-inflammatory cytokine IL-1β, abundant in MM patients' plasma, activates MSCs, whose paracrine signals are responsible for strong NF-κB activation in a minority of MM cells; iii) IL-1β, but not TNF-α, activates NF-κB in vivo in BM-engrafted MM cells, while its receptor inhibitor Anakinra reduces the global NF-κB activation. We propose that NF-κB activation in the BM of MM patients is mild, restricted to a minority of cells and modulated by the interplay of restraining physical microenvironmental cues and activating IL-1β-dependent stroma-to-MM crosstalk.

DOI: https://doi.org/10.1038/s41419-024-07038-1
Commun Biol. 2024 Oct 08. 7(1): 1282

Chemical inhibition of the integrated stress response impairs the ubiquitin-proteasome system.

Shanshan Xu, Maria E Gierisch, Enrica Barchi, Ina Poser, Simon Alberti, Florian A Salomons, Nico P Dantuma.

Inhibitors of the integrated stress response (ISR) have been used to explore the potential beneficial effects of reducing the activation of this pathway in diseases. As the ISR is in essence a protective response, there is, however, a risk that inhibition may compromise the cell's ability to restore protein homeostasis. Here, we show that the experimental compound ISRIB impairs degradation of proteins by the ubiquitin-proteasome system (UPS) during proteotoxic stress in the cytosolic, but not nuclear, compartment. Accumulation of a UPS reporter substrate that is intercepted by ribosome quality control was comparable to the level observed after blocking the UPS with a proteasome inhibitor. Consistent with impairment of the cytosolic UPS, ISRIB treatment caused an accumulation of polyubiquitylated and detergent insoluble defective ribosome products (DRiPs) in the presence of puromycin. Our data suggest that the persistent protein translation during proteotoxic stress in the absence of a functional ISR increases the pool of DRiPs, thereby hindering the efficient clearance of cytosolic substrates by the UPS.

DOI: https://doi.org/10.1038/s42003-024-06974-0
Cell Commun Signal. 2024 Oct 10. 22(1): 486

Chemoresistance and the tumor microenvironment: the critical role of cell-cell communication.

Bartosz Wilczyński, Alicja Dąbrowska, Julita Kulbacka, Dagmara Baczyńska.

  Resistance of cancer cells to anticancer drugs remains a major challenge in modern medicine. Understanding the mechanisms behind the development of chemoresistance is key to developing appropriate therapies to counteract it. Nowadays, with advances in technology, we are paying more and more attention to the role of the tumor microenvironment (TME) and intercellular interactions in this process. We also know that important elements of the TME are not only the tumor cells themselves but also other cell types, such as mesenchymal stem cells, cancer-associated fibroblasts, stromal cells, and macrophages. TME elements can communicate with each other indirectly (via cytokines, chemokines, growth factors, and extracellular vesicles [EVs]) and directly (via gap junctions, ligand-receptor pairs, cell adhesion, and tunnel nanotubes). This communication appears to be critical for the development of chemoresistance. EVs seem to be particularly interesting structures in this regard. Within these structures, lipids, proteins, and nucleic acids can be transported, acting as signaling molecules that interact with numerous biochemical pathways, thereby contributing to chemoresistance. Moreover, drug efflux pumps, which are responsible for removing drugs from cancer cells, can also be transported via EVs.

Keywords:  Cancer; Cell–cell communication; Chemoresistance; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12964-024-01857-7