bims-unfpre 2024-12-29 papers

Issue of 2024–12–29
five papers selected by
Susan Logue, University of Manitoba

Cancer Lett. 2024 Dec 20. pii: S0304-3835(24)00802-4. [Epub ahead of print]611 217407

Salivary adenoid cystic carcinoma-derived α2,6-sialylated extracellular vesicles increase vascular permeability by triggering ER-stress in endothelial cells and promote lung metastasis.

Qi Dong, Ming Dong, Xue Liu, Jiasheng Zhou, Saixuan Wu, Ziyao Liu, Weidong Niu, Tingjiao Liu.

Salivary adenoid cystic carcinoma (SACC) tends to metastasize to the lungs in the early stages of the disease. Factors secreted by the primary tumor can induce the formation of a supportive microenvironment in distant organs prior to metastasis, a process known as pre-metastatic niche (PMN) formation. Extracellular vesicles (EVs) participate in PMN formation. In this study, α2,6-sialylation of EVs derived from SACC cells with high metastatic potential increased vascular permeability, thereby facilitating tumor metastasis to the lungs. Mechanistic studies indicated that EV α2,6-sialylation triggers protein kinase R-like endoplasmic reticulum kinase (PERK)-eukaryotic initiation factor 2α (eIF2α)-dependent activation of endoplasmic reticulum (ER) stress in the endothelium, leading to the disruption of vascular endothelial cadherin membrane expression. Sialidase or an ER stress inhibitor rescued vascular permeability induced by SACC EVs, which decreased the number of SACC cells extravasating into the lungs both in vitro and in vivo. This study identified a critical role of α2,6-sialylation of SACC EVs in lung metastasis. The findings indicate that EV α2,6-sialylation-induced ER stress in endothelial cells might be a therapeutic target for preventing SACC lung metastasis.

Keywords: ER stress; Extracellular vesicles; Glycosylation; Metastasis; Pre-metastatic niche

DOI: https://doi.org/10.1016/j.canlet.2024.217407

J Biol Chem. 2024 Dec 18. pii: S0021-9258(24)02613-9. [Epub ahead of print] 108111

PRDX4 mitigates diabetic retinopathy by inhibiting reactive gliosis, apoptosis, ER stress, oxidative stress, and mitochondrial dysfunction in Müller cells.

Yue Huang, Yuting Zhang, Yuan Liu, Yinan Jin, Hongwei Yang.

Diabetic retinopathy (DR) is a neurovascular complication of diabetes. As a crucial player in the retinal physiology, Müller cells are affected in DR, impairments of Müller cell function lead to retinal malfunctions. Therefore, searching for approaches to mitigate diabetes-induced injury in Müller cells is imperative for delaying DR. Peroxiredoxin 4 (PRDX4), an important endoplasmic reticulum (ER)-resident antioxidant, was explored in this study for its potential protective role against DR. Streptozotocin (STZ)-induced mouse model of diabetes and high glucose (HG)-induced Müller cells were utilized to assess the impact of PRDX4. Compared to wild-type mice, PRDX4 knockout exacerbated retinal neurodegeneration, reactive gliosis, cell apoptosis, endoplasmic reticulum (ER) stress, oxidative stress, and mitochondrial dysfunction in diabetic retinas. Knockdown of PRDX4 aggravated high glucose (HG)-induced reactive gliosis, apoptosis, ER stress, oxidative stress, and mitochondrial dysfunction in Müller cells. Conversely, PRDX4 overexpression in Müller cells protected against HG-induced cell damage. Mechanistically, PRDX4 promoted the degradation of DPP4, which is associated with DR in type 1 diabetics, thereby alleviating HG-stimulated Müller cell abnormalities. Our study indicated that PRDX4 is a crucial protective regulator in DR progression via destabilization of DPP4 protein and suggested enhancement of PRDX4 level may represent a promising approach for treating DR.

Keywords: Müller cell; PRDX4; diabetic retinopathy; endoplasmic reticulum stress; mitochondrial dysfunction; reactive gliosis

DOI: https://doi.org/10.1016/j.jbc.2024.108111

Eur J Pharmacol. 2024 Dec 18. pii: S0014-2999(24)00900-2. [Epub ahead of print]988 177210

NRF-mediated autophagy and UPR: Exploring new avenues to overcome cancer chemo-resistance.

Sanaz Dastghaib, Sayed Mohammad Shafiee, Fatemeh Ramezani, Niloufar Ashtari, Farhad Tabasi, Javad Saffari-Chaleshtori, Morvarid Siri, Omid Vakili, Somayeh Igder, Mozhdeh Zamani, Maryam Niknam, Mahshid Moballegh Nasery, Fariba Kokabi, Emilia Wiechec, Zohreh Mostafavi-Pour, Pooneh Mokarram, Saeid Ghavami.

The development of chemo-resistance remains a significant hurdle in effective cancer therapy. NRF1 and NRF2, key regulators of redox homeostasis, play crucial roles in the cellular response to oxidative stress, with implications for both tumor growth and resistance to chemotherapy. This study delves into the dualistic role of NRF2, exploring its protective functions in normal cells and its paradoxical support of tumor survival and drug resistance in cancerous cells. We investigate the interplay between the PERK/NRF signaling pathway, ER stress, autophagy, and the unfolded protein response, offering a mechanistic perspective on how these processes contribute to chemoresistance. Our findings suggest that targeting NRF signaling pathways may offer new avenues for overcoming resistance to chemotherapeutic agents, highlighting the importance of a nuanced approach to redox regulation in cancer treatment. This research provides a molecular basis for the development of NRF-targeted therapies, potentially enhancing the efficacy of existing cancer treatments and offering hope for more effective management of resistant tumors.

Keywords: Autophagy; Drug resistance; NF-E2-related factor 2; Reactive oxygen species; Unfolded protein response

DOI: https://doi.org/10.1016/j.ejphar.2024.177210

Inflammation. 2024 Dec 23.

Exosomes Derived from Endoplasmic Reticulum Stressed Hepatocellular Carcinoma Cells Enhance the Antitumor Immunity of Dendritic Cells.

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

Endoplasmic reticulum stress (ERs) is implicated in antitumor immunity. However, the exact role of ERs in mediating the effects of dendritic cells (DCs) is not unclear. In this study, we explored the role of exosomes derived from ER-stressed hepatocellular carcinoma (HCC) cells in the antitumor effects of DCs and the precise underlying mechanism. We found that ER-stressed HCC cells secreted more exosomes (EXO-TM) than those without ER stress (EXO-CON) and that exosomes were effectively taken up by DCs. EXO-TM significantly promoted DCs maturation, as demonstrated by the increased expression of HLA-ABC, CD83, CD80, CD86, and pro-inflammatory cytokines and the decreased expression of IL-10. Moreover, EXO-TM pulsed DCs (DCEXO-TM) significantly enhanced T lymphocyte-mediated lysis against several types of tumor cells by promoting the proliferation of CD3+CD8+ T cells and increasing the expression of INF-γ both in vitro and in vivo. Mechanistically, we found that heat shock protein (HSP) 90 was more significantly enriched in EXO-TM than in EXO-CON cells, and the knockdown of HSP90 remarkably reversed EXO-TM-mediated DC activation. Our results suggest that exosomes derived from ER-stressed HCC cells could enhance the antitumor effect of DC-mediated T lymphocytes, which may be related to the large amount of HSP90 carried in the exosomes. Therefore, regulating the HSP90 carrying capacity of tumor exosomes may be an effective immunotherapy strategy.

Keywords: Anti-tumor immunity; Dendritic cell; Endoplasmic reticulum stress; Exosomes; Hepatocellular carcinoma

DOI: https://doi.org/10.1007/s10753-024-02214-z

Cell Mol Life Sci. 2024 Dec 24. 82(1): 13

Trimethylamine-N-oxide accelerates osteoporosis by PERK activation of ATF5 unfolding.

Yu-Han Lin, Wei-Shiung Lian, Re-Wen Wu, Yu-Shan Chen, Shin-Long Wu, Jih-Yang Ko, Shao-Yu Wang, Holger Jahr, Feng-Sheng Wang.

Imbalances in gut microbiota and their metabolites have been implicated in osteoporotic disorders. Trimethylamine-n-oxide (TMAO), a metabolite of L-carnitine produced by gut microorganisms and flavin-containing monooxygenase-3, is known to accelerate tissue metabolism and remodeling; however, its role in bone loss remained unexplored. This study investigates the relationship between gut microbiota dysbiosis, TMAO production, and osteoporosis development. We further demonstrate that the loss of beneficial gut microbiota is associated with the development of murine osteoporosis and alterations in the serum metabolome, particularly affecting L-carnitine metabolism. TMAO emerges as a functional metabolite detrimental to bone homeostasis. Notably, transplantation of mouse gut microbiota counteracts obesity- or estrogen deficiency-induced TMAO overproduction and mitigates key features of osteoporosis. Mechanistically, excessive TMAO intake augments bone mass loss by inhibiting bone mineral acquisition and osteogenic differentiation. TMAO activates the PERK and ATF4-dependent disruption of endoplasmic reticulum autophagy and suppresses the folding of ATF5, hindering mitochondrial unfolding protein response (UPRmt) in osteoblasts. Importantly, UPRmt activation by nicotinamide riboside mitigates TMAO-induced inhibition of mineralized matrix biosynthesis by preserving mitochondrial oxidative phosphorylation and mitophagy. Collectively, our findings revealed that gut microbiota dysbiosis leads to TMAO overproduction, impairing ER homeostasis and UPRmt, thereby aggravating osteoblast dysfunction and development of osteoporosis. Our study elucidates the catabolic role of gut microflora-derived TMAO in bone integrity and highlights the therapeutic potential of healthy donor gut microbiota transplantation to alter the progression of osteoporosis.

Keywords: ER-phagy; Gut microecosystem; Misfolding; OXPHOS; Parkin; Trimethylamine-n-oxide

DOI: https://doi.org/10.1007/s00018-024-05501-y