Evaluating lactate metabolism for prognostic assessment and therapy response prediction in gastric cancer with emphasis on the oncogenic role of SLC5A12

Article

Author: Xu, Yining ; Xu, Chao ; Lin, Jia ; Zheng, Ying ; Li, Feng ; Wang, Qingshui ; Lin, Chenyi ; Lin, Yao ; Chen, Yuluo ; Chi, Liangjie ; Ye, Jianjian

BACKGROUNDGastric cancer remains a common malignancy with poor prognosis. While lactate metabolism is recognized as a significant factor in tumor progression, its potential as a predictive tool for treatment response remains unexplored. This study introduces a novel Lactate-Related Gene Signature (LRGS) designed to predict both survival outcomes and therapy responses in gastric cancer patients.METHODSWe comprehensively analyzed 335 lactate-related genes from 11 metabolic pathways using MSigDB, identifying 278 differentially expressed genes between gastric cancer and normal tissues. Employing the LASSO Cox regression model, we developed an innovative LRGS formula based on the expression of 16 key lactate-related genes. The impact of Solute Carrier Family 5 Member 12 (SLC5A12), a gene of particular interest, on gastric cancer cell functions was evaluated using in vitro assays and an in vivo zebrafish model.RESULTSOur newly established LRGS demonstrated robust capability in stratifying gastric cancer patients by survival risk. Notably, the LRGS-low subtype showed significantly improved overall and disease-free survival rates compared to the LRGS-high subtype. A key finding was LRGS's ability to predict patient responses to both adjuvant chemotherapy and immunotherapy. Random forest analysis identified SLC5A12 as the most significant gene differentiating gastric cancer from normal tissues. Functional experiments confirmed SLC5A12's role in promoting gastric cancer cell proliferation, invasion, and migration both in vitro and in vivo.CONCLUSIONThe LRGS is a dependable and efficient prognostic tool for assessing the survival outcomes in individuals with gastric cancer, as well as a predictor of patient response to adjuvant chemotherapy and immunotherapy.

01 Apr 2023·Pharmacological Reports

An in vitro evaluation of the antioxidant activities of necroptosis and apoptosis inhibitors: the potential of necrostatin-1 and necrostatin-1i to have radical scavenging activities

Article

Author: Monzaki, Rina ; Ushijima, Hironori

BACKGROUNDNecroptosis inhibitors, including necrostatin-1 (Nec-1), are attracting attention as potential therapeutic agents against various diseases, such as acute lung injury, chronic obstructive pulmonary disease, acute kidney injury, nonalcoholic fatty liver, and neurodegenerative disease, where necroptosis is thought to act as a contributing factor. Nec-1 suppresses necroptosis by inhibiting receptor-interacting protein (RIP) 1 kinase and can also reduce reactive oxygen species (ROS) production; however, the underlying molecular mechanisms mediating ROS reduction remain unclear.METHODSThe antioxidant effects of necroptosis inhibitors, including Nec-1 and apoptosis inhibitors, were quantified by performing a 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging assay. Nec-1-related compounds were subsequently assayed for cupric ion-reducing capacity and superoxide dismutase (SOD)-like activity.RESULTSConsidering all examined apoptosis and necroptosis inhibitors, Nec-1and Nec-1i exhibited antioxidant activity in DPPH radical scavenging assay. In the cupric ion-reducing capacity assay, Nec-1i showed stronger antioxidant capacity than Nec-1. In the SOD-like activity assay, both Nec-1 and Nec-1i were found to have stronger antioxidant capacity than ascorbic acid (IC₅₀ = 4.6 ± 0.040 and 61 ± 0.54 µM, respectively).CONCLUSIONThese results suggest that Nec-1 and Nec-1i may exhibit direct radical scavenging ability against superoxide anions, independent of RIP1 inhibition.

23 Nov 2021·Proceedings of the National Academy of SciencesQ1 · CROSS-FIELD

Lipofuscin causes atypical necroptosis through lysosomal membrane permeabilization

Q1 · CROSS-FIELD

Article

Author: Benedicto, Ignacio ; Rodriguez-Boulan, Enrique ; Hajjar, Katherine A. ; Banerjee, Kalpita ; Lehmann, Guillermo L. ; Almeida, Dena ; Radu, Roxana A. ; Nociari, Marcelo M. ; Jiang, Zhichun ; Pan, Chendong ; Thompson, David H.

Lipofuscin granules enclose mixtures of cross-linked proteins and lipids in proportions that depend on the tissue analyzed. Retinal lipofuscin is unique in that it contains mostly lipids with very little proteins. However, retinal lipofuscin also presents biological and physicochemical characteristics indistinguishable from conventional granules, including indigestibility, tendency to cause lysosome swelling that results in rupture or defective functions, and ability to trigger NLRP3 inflammation, a symptom of low-level disruption of lysosomes. In addition, like conventional lipofuscins, it appears as an autofluorescent pigment, considered toxic waste, and a biomarker of aging. Ocular lipofuscin accumulates in the retinal pigment epithelium (RPE), whereby it interferes with the support of the neuroretina. RPE cell death is the primary cause of blindness in the most prevalent incurable genetic and age-related human disorders, Stargardt disease and age-related macular degeneration (AMD), respectively. Although retinal lipofuscin is directly linked to the cell death of the RPE in Stargardt, the extent to which it contributes to AMD is a matter of debate. Nonetheless, the number of AMD clinical trials that target lipofuscin formation speaks for the potential relevance for AMD as well. Here, we show that retinal lipofuscin triggers an atypical necroptotic cascade, amenable to pharmacological intervention. This pathway is distinct from canonic necroptosis and is instead dependent on the destabilization of lysosomes. We also provide evidence that necroptosis is activated in aged human retinas with AMD. Overall, this cytotoxicity mechanism may offer therapeutic targets and markers for genetic and age-related diseases associated with lipofuscin buildups.

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