Growth or death? Control of cell destiny by mTOR and autophagy pathways.

One of the central regulators of cell growth, proliferation, and metabolism is the mammalian target of rapamycin, mTOR, which exists in two structurally and functionally different complexes: mTORC1 and mTORC2; unlike m TORC2, mTORC1 is activated in response to the sufficiency of nutrients and is inhibited by rapamycin. mTOR complexes have critical roles not only in protein synthesis, gene transcription regulation, proliferation, tumor metabolism, but also in the regulation of the programmed cell death mechanisms such as autophagy and apoptosis. Autophagy is a conserved catabolic mechanism in which damaged molecules are recycled in response to nutrient starvation. Emerging evidence indicates that the mTOR signaling pathway is frequently activated in tumors. In addition, dysregulation of autophagy was associated with the development of a variety of human diseases, such as cancer and aging. Since mTOR can inhibit the induction of the autophagic process from the early stages of autophagosome formation to the late stage of lysosome degradation, the use of mTOR inhibitors to regulate autophagy could be considered a potential therapeutic option. The present review sheds light on the mTOR and autophagy signaling pathways and the mechanisms of regulation of mTOR-autophagy.

Differential Gene Expression Signatures and Cellular Signaling Pathways induced by Lamin A/C Transcript Variants in MCF7 Cell Line.

BACKGROUND: Lamins are the major component of nuclear lamina. Alternative splicing of the 12 exons comprising lamin A/C gene creates five known transcript variants, lamin A, lamin C, lamin AΔ10, lamin AΔ50, and lamin C2. The main objective for this study was to examine the association of critical pathways, networks, molecular and cellular functions regulated by each Lamin A/C transcript variants. METHODS: Ion AmpliSeq Transcriptome Human Gene Expression analysis was performed on MCF7 cells stably transfected with lamin A/C transcript variants. RESULTS: Lamin A or lamin AΔ50 upregulation was associated with activation of cell death and inactivation of carcinogenesis while both lamin C or lamin AΔ10 upregulation activated carcinogenesis and cell death. CONCLUSIONS: Data suggest anti-apoptotic and anti-senescence effects of lamin C and lamin AΔ10 as several functions, including apoptosis and necrosis functions are inactivated following lamin C or lamin AΔ10 upregulation. However, lamin AΔ10 upregulation is associated with a more carcinogenic and aggressive tumor phenotype. Lamin A or lamin AΔ50 upregulation is associated with a predicted activation of increased cell death and inactivation of carcinogenesis. Thus, different signaling pathways, networks, molecular and cellular functions are activated/inactivated by lamin A/C transcript variants resulting in a large number of laminopathies.

Association of VKORC1 and CYP2C9 single-nucleotide polymorphisms with warfarin dose adjustment in Saudi patients.

OBJECTIVES: Despite its wide usage, warfarin therapy remains challenging due to its narrow therapeutic index, inter-individual response variability, and risk of bleeding. Previous reports have suggested that polymorphisms in VKORC1 and CYP2C9 genes could influence warfarin therapy. Herein, we investigated whether VKORC1 -1173C>T, CYP2C9*2, and CYP2C9*3 gene polymorphisms are associated with warfarin dose adjustment and related bleeding events. METHODS: This cross-sectional study was conducted on Saudi adults receiving warfarin for more than 1 month. Their demographics and relevant clinical data were obtained. Genotyping for VKORC1 -1173C>T, CYP2C9*2, and CYP2C9*2 genotypes was performed. RESULTS: Patients who are homozygous for the mutant T allele VKORC1 T/T required the lowest warfarin daily maintenance dose, compared to VKORC1 C/T and VKORC1 C/C. Similarly, there was a significant reduction in warfarin daily maintenance dose among CYP2C9*1/*3 and CYP2C9*1/*2 groups compared to CYP2C9*1/*1. However, we found no significant correlation between the studied polymorphisms and warfarin-associated bleeding. CONCLUSIONS: Similar to other populations, the VKORC1 and CYP2C9 gene polymorphisms are significantly associated with warfarin dosage in Saudi patients. The presence of at least one copy of the mutant alleles for VKORC1 -1173C>T, CYP2C9*2, and CYP2C9*3 is associated with a significant reduction in warfarin maintenance dose.

Association of VKORC1 and CYP2C9 single-nucleotide polymorphisms with warfarin dose adjustment in Saudi patients.

OBJECTIVES: Despite its wide usage, warfarin therapy remains challenging due to its narrow therapeutic index, inter-individual response variability, and risk of bleeding. Previous reports have suggested that polymorphisms in VKORC1 and CYP2C9 genes could influence warfarin therapy. Herein, we investigated whether VKORC1 -1173C>T, CYP2C9*2, and CYP2C9*3 gene polymorphisms are associated with warfarin dose adjustment and related bleeding events. METHODS: This cross-sectional study was conducted on Saudi adults receiving warfarin for more than 1 month. Their demographics and relevant clinical data were obtained. Genotyping for VKORC1 -1173C>T, CYP2C9*2, and CYP2C9*2 genotypes was performed. RESULTS: Patients who are homozygous for the mutant T allele VKORC1 T/T required the lowest warfarin daily maintenance dose, compared to VKORC1 C/T and VKORC1 C/C. Similarly, there was a significant reduction in warfarin daily maintenance dose among CYP2C9*1/*3 and CYP2C9*1/*2 groups compared to CYP2C9*1/*1. However, we found no significant correlation between the studied polymorphisms and warfarin-associated bleeding. CONCLUSIONS: Similar to other populations, the VKORC1 and CYP2C9 gene polymorphisms are significantly associated with warfarin dosage in Saudi patients. The presence of at least one copy of the mutant alleles for VKORC1 -1173C>T, CYP2C9*2, and CYP2C9*3 is associated with a significant reduction in warfarin maintenance dose.