RESUMO
Epitranscriptomic modification of tRNA has recently gained traction in the field of cancer biology. The presence of such modifications on tRNA appears to allow for translational control of processes central to progression and malignant transformation. Methyltransferase Like 1 protein (METTL1), along with other epitranscriptomic writers (e.g. NSUN3, NAT10, ELP3, etc.), has recently been investigated in multiple cancer types. Here, we review the impact of such tRNA modifications in tumorigenesis and the progression of cancer toward drug resistance and metastasis. Regulation of central cellular processes relied upon by malignant cancer cells through modulation of the tRNA epitranscriptome represents an area with great potential to bring novel first-in-class therapies to the clinic.
Assuntos
Neoplasias , RNA de Transferência , Humanos , RNA de Transferência/genética , RNA de Transferência/metabolismo , Neoplasias/genética , Neoplasias/patologia , Progressão da Doença , Processamento Pós-Transcricional do RNA/genética , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , AnimaisRESUMO
Metastasizing cancer cells encounter a multitude of stresses throughout the metastatic cascade. Oxidative stress is known to be a major barrier for metastatic colonization, such that metastasizing cancer cells must rewire their metabolic pathways to increase their antioxidant capacity. NADPH is essential for regeneration of cellular antioxidants and several NADPH-regenerating pathways have been shown to play a role in metastasis. We have found that metastatic melanoma cells have increased levels of both NADPH and NADP+ suggesting increased de novo biosynthesis of NADP+. De novo biosynthesis of NADP+ occurs through a single enzymatic reaction catalyzed by NAD+ kinase (NADK). Here we show that different NADK isoforms are differentially expressed in metastatic melanoma cells, with Isoform 3 being specifically upregulated in metastasis. We find that Isoform 3 is more potent in expanding the NADP(H) pools, increasing oxidative stress resistance and promoting metastatic colonization compared to Isoform 1. We have found that Isoform 3 is transcriptionally upregulated by oxidative stress through the action of NRF2. Together, our work presents a previously uncharacterized role of NADK isoforms in oxidative stress resistance and metastasis and suggests that NADK Isoform 3 is a potential therapeutic target in metastatic disease.
Assuntos
Regulação Neoplásica da Expressão Gênica , Isoenzimas , Melanoma , Fator 2 Relacionado a NF-E2 , Metástase Neoplásica , Estresse Oxidativo , Fosfotransferases (Aceptor do Grupo Álcool) , Melanoma/metabolismo , Melanoma/patologia , Melanoma/genética , Humanos , Animais , Isoenzimas/metabolismo , Isoenzimas/genética , Camundongos , Linhagem Celular Tumoral , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/genética , NADP/metabolismoRESUMO
Cytochrome P450s are key players in drug metabolism, and overexpression in tumors is associated with significant resistance to many medicinal agents. Consequently, inhibition of P450s could serve as a strategy to restore drug efficacy. However, the widespread expression of P450s throughout the human body and the critical roles they play in various biosynthetic pathways motivates the development of P450 inhibitors capable of controlled local administration. Ruthenium complexes containing P450 inhibitors as ligands were synthesized in order to develop pro-drugs that can be triggered to release the inhibitors in a spatially and temporally controlled fashion. Upon light activation the compounds release ligands that directly bind and inhibit P450 enzymes, while the ruthenium center is able to directly damage DNA.