bims-istrec 2022-11-06 papers

bims-istrec

Biomed News

on Integrated stress response in cancer

Issue of 2022–11–06
six papers selected by
the Vincenzo Ciminale lab, Istituto Oncologico Veneto

Exosomal NAMPT from chronic lymphocytic leukemia cells orchestrate monocyte survival and phenotype under endoplasmic reticulum stress.
Endoplasmic Reticulum Stress and Metabolism in Hepatocellular Carcinoma.
Translational alterations in pancreatic cancer: a central role for the integrated stress response.
Ornidazole suppresses CD133+ melanoma stem cells via inhibiting hedgehog signaling pathway and inducing multiple death pathways in a mouse model.
Aryl-, halogenated- and alkyl- organophosphate esters induced oxidative stress, endoplasmic reticulum stress and NLRP3 inflammasome activation in HepG2 cells.
The regulatory mechanism of HSP70 in endoplasmic reticulum stress in pepsin-treated laryngeal epithelium cells and laryngeal cancer cells.

Hematol Oncol. 2022 Nov 02.

Exosomal NAMPT from chronic lymphocytic leukemia cells orchestrate monocyte survival and phenotype under endoplasmic reticulum stress.

Jing Ni, Ju Zhang, Jiatao Liu, Lulu Fan, Xiao Lin, Hanqing Yu, Guoping Sun.

  Endoplasmic reticulum (ER) stress has been reported to be transmissible from tumor cells to immune cells via exosome and implicated in immune escape. However, the influence of ER stress in chronic lymphocytic leukemia (CLL) cells on monocytes is largely unknown. Here, we observed the expression of ER stress markers (GRP78, ATF6, PERK, IRE1a, and XBP1s) in CLL cells. The increasing mRNA expression of these ER stress response components was positively correlated with more aggressive disease. Exosome from ER stress inducer tunicamycin (TM)-primed CLL cells (ERS-exo) up-regulated the expression of ER stress marker on monocytes, indicating ER stress is transmissible in vitro via exosome. Treatment with ERS-exo promoted the survival of monocytes and induced phenotypic changes with a significantly larger percentage of CD14+ CD16+ monocytes. Finally, we identified exosome-mediated transfer of extracellular nicotinamide phosphoribosyltransferase (eNAMPT) from ER stressed CLL cells into monocytes as a novel mechanism through which ERS-exo regulated monocytes. Exosomal eNAMPT up-regulated nicotinamide adenine dinucleotide (NAD+ ) production which subsequently activated SIRT1-C/EBPβ signaling pathway in monocytes. Our results suggest the role of ER stress in mediating immunological dysfunction in CLL. This article is protected by copyright. All rights reserved.

Keywords:  Chronic lymphocytic leukemia; Endoplasmic reticulum (ER) stress

DOI:  https://doi.org/10.1002/hon.3093
Am J Pathol. 2022 Oct 26. pii: S0002-9440(22)00322-4. [Epub ahead of print]

Endoplasmic Reticulum Stress and Metabolism in Hepatocellular Carcinoma.

Clara Luna-Marco, Anna Ubink, Maria Kopsida, Femke Heindryckx.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, accounting for 85-90% of all liver cancer cases. It is a hepatocyte-derived primary tumour, causing 550,000 deaths per year, ranking it as one of the most common cancers worldwide. The liver is a highly metabolic organ with multiple functions, including digestion, detoxification, breakdown of fats, production of bile and cholesterol, in addition to storage of vitamins, glycogen and minerals, and synthesizing plasma proteins and clotting factors. Due to these fundamental and diverse functions, the malignant transformation of hepatic cells can have a severe impact on the liver´s metabolism. Furthermore, tumorigenesis is often accompanied by an activation of the endoplasmic reticulum (ER) stress pathways, which are known to be highly intertwined with several metabolic pathways. As HCC is characterized by changes in the metabolome and by an aberrant activation of the ER-stress pathways, the aim of this review is to summarize the available knowledge that links ER-stress and metabolism in HCC, thereby focusing on potential therapeutic targets.

DOI: https://doi.org/10.1016/j.ajpath.2022.09.012
NAR Cancer. 2022 Dec;4(4): zcac031

Translational alterations in pancreatic cancer: a central role for the integrated stress response.

Sauyeun Shin, Jacobo Solorzano, Mehdi Liauzun, Stéphane Pyronnet, Corinne Bousquet, Yvan Martineau.

mRNA translation is a key mechanism for cancer cell proliferation and stress adaptation. Regulation of this machinery implicates upstream pathways such as PI3K/AKT/mTOR, RAS/MEK/ERK and the integrated stress response (ISR), principally coordinating the translation initiation step. During the last decade, dysregulation of the mRNA translation process in pancreatic cancer has been widely reported, and shown to critically impact on cancer initiation, development and survival. This includes translation dysregulation of mRNAs encoding oncogenes and tumor suppressors. Hence, cancer cells survive a stressful microenvironment through a flexible regulation of translation initiation for rapid adaptation. The ISR pathway has an important role in chemoresistance and shows high potential therapeutic interest. Despite the numerous translational alterations reported in pancreatic cancer, their consequences are greatly underestimated. In this review, we summarize the different translation dysregulations described in pancreatic cancer, which make it invulnerable, as well as the latest drug discoveries bringing a glimmer of hope.

DOI: https://doi.org/10.1093/narcan/zcac031
Croat Med J. 2022 Oct 31. 63(5): 461-474

Ornidazole suppresses CD133+ melanoma stem cells via inhibiting hedgehog signaling pathway and inducing multiple death pathways in a mouse model.

Gulsah Evyapan, Umit Luleyap, Halil Mahir Kaplan, Ismail Oguz Kara.

AIM: To evaluate the inhibitory effects of ornidazole on the proliferation and migration of metastatic melanoma cell line (B16F10) in vitro and its anti-cancer effects in vivo using a melanoma mouse model.
METHODS: We investigated the effects of ornidazole on cell viability (Crystal Violet and MTT assay) and migration ability (wound-healing assay) of B16F10 melanoma cells, and its ability to trigger DNA damage (Comet assay) in vitro. We also sorted CD133+ and CD133- cells from B16F10 melanoma cell line and injected them subcutaneously into Swiss albino mice to induce tumor formation. Tumor-bearing mice were divided into control and treatment groups. Treatment group received intraperitoneal ornidazole injections. Tumors were resected. Real-time polymerase chain reaction was used to determine the expression of genes involved into Sonic hedgehog (Shh) signaling pathway, stemness, apoptosis, endoplasmic reticulum (ER) stress, ER stress-mediated apoptosis, and autophagy. Shh signaling pathway-related proteins and CD133 protein were analyzed by ELISA.
RESULTS: Ornidazole effectively induced DNA damage in CD133+ melanoma cells and reduced their viability and migration ability in vitro. Moreover, it significantly suppressed tumor growth in melanoma mouse model seemingly by inhibiting the Shh signaling pathway and ER-stress mediated autophagy, as well as by activating multiple apoptosis pathways.
CONCLUSIONS: Our preclinical findings suggest the therapeutic potential of ornidazole in the treatment of metastatic melanoma. However, larger and more comprehensive studies are required to validate our results and to further explore the safety and clinical effectiveness of ornidazole.
Environ Pollut. 2022 Oct 31. pii: S0269-7491(22)01773-0. [Epub ahead of print] 120559

Aryl-, halogenated- and alkyl- organophosphate esters induced oxidative stress, endoplasmic reticulum stress and NLRP3 inflammasome activation in HepG2 cells.

Yuanyuan Zhou, Hanyu Liao, Shanshan Yin, Pengqiao Wang, Xiaoqing Ye, Jianyun Zhang.

  Organophosphate esters (OPEs) are a group of extensively used man-made chemicals with diverse substituents that are ubiquitously detected in human-related samples including serum, breastmilk, food and house dust. The understanding of their toxicological effects and potential mechanisms on hepatocytes is still limited. In this study, nine most frequently detected OPEs were selected and divided into three subgroups (aryl-, halogenated- and alkyl-OPEs) based on their substituents. The cytotoxicity, apoptosis, oxidative stress, endoplasmic reticulum (ER) stress and NLRP3 inflammasome activation induced by OPEs were evaluated in human hepatocellular carcinomas HepG2 cells. All OPEs induced apoptosis likely through a caspase-dependent apoptotic pathway. The activities of anti-oxidative enzyme SOD and CAT exhibited sensitive responses after OPEs treatment for 6 h. The OPEs induced ROS overproduction, DNA damage, endoplasmic reticulum (ER) stress and NLRP3 inflammasome activation varied among aryl-, halogenated- and alkyl-OPEs. Halogenated- and alkyl- OPEs induced overproduction of ROS and DNA damage, and elevated ER stress and NLRP3 inflammasome activation are observed aryl-OPEs induced cytotoxicity.

Keywords:  Cytotoxicity; Endoplasmic reticulum stress; NLRP3 inflammasome; Organophosphorus esters; Oxidative stress

DOI:  https://doi.org/10.1016/j.envpol.2022.120559
Aging (Albany NY). 2022 Oct 27. 14(undefined):

The regulatory mechanism of HSP70 in endoplasmic reticulum stress in pepsin-treated laryngeal epithelium cells and laryngeal cancer cells.

Wei Chen, Zhiyi Wang, Junfeng Ji, Tao Shi, Hong Ye Jiao, You Cheng, Li Xu, Rui Wang.

   BACKGROUNDS: Excessive pepsin can damage both normal laryngeal epithelial cells and laryngeal cancer (LC) cells. Heat shock protein 70 (HSP70) is closely related to pepsin. In this paper, we will explore the different significance of the regulatory role of HSP70 in endoplasmic reticulum stress (ERS) level in pepsin-treated laryngeal epithelial cells and LC cells.
METHODS: In cell experiments, laryngeal epithelial cells and LC cells were selected and induced by different concentrations of pepsin. Cell activity was detected by CCK8, cell apoptosis was detected by flow cytometry, and autophagy was detected by autophagy detection kit. The expression of ER)-related proteins was detected by immunofluorescence (IF) and Western blot. Cell transfection was used to inhibit HSP70 expression in both cells, and ERS, apoptosis, and autophagy were measured using related techniques. In animal experiments, a mouse model bearing LC was established. TUNEL assay detected apoptosis, autophagy kit detected autophagy, and ER-related protein expression was detected by Western blot.
RESULTS: HSP70 was increased in pepsin-stimulated laryngeal epithelial cells and LC cells, thereby inhibiting ER and ER-induced apoptosis and autophagy. Inhibition of HSP70 reduced the expression of glucose regulated protein 78 (GRP78) in pepsin-stimulated laryngeal epithelial cells and LC cells, and only inhibited downstream apoptosis-related pathways in laryngeal epithelial cells rather than in LC cells. Inhibition of HSP70 and ER could significantly promote apoptosis and inhibit tumor growth in the absence of pepsin stimulation in vivo.
CONCLUSION: ER level regulated by HSP70 had different significance in laryngeal epithelial cells and LC cells treated with pepsin.

Keywords:  HSP70; apoptosis; autophagy; endoplasmic reticulum stress; laryngeal cancer

DOI:  https://doi.org/10.18632/aging.204356