RNA expression profiling in sulfamethoxazole‐treated patients with a range of in vitro lymphocyte cytotoxicity phenotypes

Abstract

The lymphocyte toxicity assay (LTA) is a proposed surrogate marker of sulfonamide antibiotic hypersensitivity. In the LTA, peripheral blood mononuclear cells (PBMCs) undergo apoptosis more readily in hypersensitive versus tolerant patients when exposed to drug‐hydroxylamine metabolites in vitro. The purpose of this study was to identify key gene transcripts associated with increased cytotoxicity from sulfamethoxazole‐hydroxylamine in human PBMCs in the LTA. The LTA was performed on PBMCs of 10 patients hypersensitive to trimethoprim‐sulfamethoxazole (HS) and 10 drug‐tolerant controls (TOL), using two cytotoxicity assays: YO‐PRO (n = 20) and MTT (n = 12). mRNA expression profiles of PBMCs, enriched for CD8+ T cells, were compared between HS and TOL patients. Transcript expression was interrogated for correlation with % cytotoxicity from YO‐PRO and MTT assays. Correlated transcripts of interest were validated by qPCR. LTA results were not significantly different between HS and TOL patients, and no transcripts were found to be differentially expressed between the two groups. 96 transcripts were correlated with cytotoxicity by YO‐PRO (r = ±.63‐.75, FDR 0.188). Transcripts were selected for validation based on mechanistic plausibility and three were significantly over‐expressed by qPCR in high cytotoxicity patients: multi‐specific organic anion transporter C (ABCC5), mitoferrin‐1 (SLC25A37), and Porimin (TMEM123). These data identify novel transcripts that could contribute to sulfonamide‐hydroxylamine induced cytotoxicity. These include SLC25A37, encoding a mitochondrial iron transporter, ABCC5, encoding an arylamine drug transporter, and TMEM123, encoding a transmembrane protein that mediates cell death.

The expression characteristics of transmembrane protein genes in pancreatic ductal adenocarcinoma through comprehensive analysis of bulk and single-cell RNA sequence

“…TMEM176B inhibits NLRP3 inflammasome activation to regulate adaptive and innate antitumor responses, suggesting that TMEM176 may be a potential immunotherapy target for pancreatic cancer ( 47 ). Additionally, numerous studies have shown that TMEM123 and TMEM66 in T cells, and TMEM208, TMEM59, and TMEM258 in B cells, are closely related to inflammatory response and participate in tumor immune response, which is consistent with our findings ( 48 – 50 ).…”

“…Additionally, numerous studies have shown that TMEM123 and TMEM66 in T cells, and TMEM208, TMEM59, and TMEM258 in B cells, are closely related to inflammatory response and participate in tumor immune response, which is consistent with our findings (48)(49)(50).…”

Non-coding RNAs in necroptosis, pyroptosis and ferroptosis in cancer metastasis

“…In rhabdomyosarcoma (RMS), miR-7 showed the anti-tumor effect to induce necroptosis by targeting mitochondrial proteins SLC25A37 and TIMM50 [ 32 ]. SLC25A37 was significantly over-expressed in high cytotoxicity patients [ 33 ] and loss of TIM50 suppressed tumor cell growth and induced apoptosis in breast cancer [ 34 ] and loss of TIM50 suppressed tumor cell growth and induced apoptosis in breast cancer [ 35 ]. Several miRNAs were reported to regulate necroptosis by targeting and regulating RIP-1.…”

Development of a necroptosis-related prognostic model for uterine corpus endometrial carcinoma

“…In rhabdomyosarcoma (RMS), miR-7 exerts an anti-tumor effect by targeting mitochondrial proteins SLC25A37 and TIMM50, ultimately inducing necrosis 35 . Moreover, SLC25A37 is significantly overexpressed in patients with high cytotoxicity 36 , while TIM50 deficiency suppresses tumor cell growth and induces apoptosis in breast cancer 37 . Based on the findings of these previous investigations, the two miRNAs identified in our study, which markedly impact the survival of UCEC patients, are also closely associated with prognosis in other malignancies.…”