BACKGROUND. The isolated recurrence of testicular leukemia in boys with acuteHenk van den Berg, M.D., Ph.D. 1 lymphoblastic leukemia (ALL) is considered to be an ominous sign, heralding
Patients with urothelial carcinoma frequently fail to respond to first-line chemotherapy using cisplatin and gemcitabine due to development of resistant tumor cells. The aim of the present study was to investigate whether an alternative treatment with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) that induces tumor cell death via the extrinsic apoptotic pathway may be effective against chemotherapy-resistant urothelial cancer cell lines. The viability of the urothelial cancer cell line RT112 and its chemotherapy-adapted sublines was investigated by MTT assay. The expression of anti-apoptotic proteins was determined by western blotting and the individual roles of cellular inhibitor of apoptosis protein (cIAP)1, cIAP2, x-linked inhibitor of apoptosis protein (XIAP) and induced myeloid leukemia cell differentiation protein (Mcl-1) were investigated by siRNA-mediated depletion. In particular, the bladder cancer sublines that were resistant to gemcitabine and cisplatin were cross-resistant to TRAIL. Resistant cells displayed upregulation of anti-apoptotic molecules compared with the parental cell line. Treatment with the second mitochondrial activator of caspases (SMAC) mimetic LCL-161 that antagonizes cIAP1, cIAP2 and XIAP resensitized chemoresistant cells to TRAIL. The resensitization of tumor cells to TRAIL was confirmed by depletion of antiapoptotic proteins with siRNA. Collectively, the findings of the present study demonstrated that SMAC mimetic LCL-161 increased the sensitivity of the parental cell line RT112 and chemotherapy-resistant sublines to TRAIL, suggesting that inhibiting anti-apoptotic molecules renders TRAIL therapy highly effective for chemotherapy-sensitive and -resistant urothelial cancer cells.
Alzheimers Disease (AD) is a progressive and irreversible neurodegenerative disorder, characterized by the accumulation of β-amyloid aggregates, which triggers tau hyperphosphorylation and neuronal loss. While the precise mechanisms underlying neurodegeneration in AD are not entirely understood, it is known that loss of proteostasis is implicated in this process. Maintaining neuronal proteostasis requires proper transfer RNA (tRNA) modifications, which are crucial for optimal translation. However, research into tRNA epitranscriptome in AD is limited, and it is not yet clear how alterations in tRNA modifying enzymes and tRNA modifications might contribute to disease progression. Here, we report that expression of the tRNA modifying enzyme ELP3 is reduced in the brain of AD patients and amyloid AD mouse models, suggesting ELP3 is implicated in proteostasis dysregulation observed in AD. To investigate the role of ELP3 specifically in neuronal proteostasis impairments in the context of amyloid pathology, we analyzed SH-SY5Y neuronal cells carrying the amyloidogenic Swedish familial AD mutation in the APP gene (SH-SWE) or the wild-type gene (SH-WT). Similarly to the amyloid mouse models, SH-SWE exhibited reduced levels of ELP3 which was associated with tRNA hypomodifications and reduced abundance, as well as proteostasis impairments. Furthermore, the knock-down of ELP3 in SH-WT recapitulated the proteostasis impairments observed in SH-SWE cells. Importantly, the correction of tRNA deficits due to ELP3 reduction rescued and reverted proteostasis impairments of SH-SWE and SH-WT knock-down for ELP3, respectively. Additionally, SH-WT exposed to the secretome of SH-SWE or synthetic amyloid aggregates recapitulate the SH-SWE phenotype, characterized by reduced ELP3 expression, tRNA hypomodification and increased protein aggregation. Taken together, our data suggest that amyloid pathology dysregulates neuronal proteostasis through the reduction of ELP3 and tRNA modifications. This study highlights the modulation of tRNA modifications as a potential therapeutic avenue to restore neuronal proteostasis in AD and preserve neuronal function.
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