Microbial and Natural Metabolites That Inhibit Splicing: A Powerful Alternative for Cancer Treatment

Abstract

In eukaryotes, genes are frequently interrupted with noncoding sequences named introns. Alternative splicing is a nuclear mechanism by which these introns are removed and flanking coding regions named exons are joined together to generate a message that will be translated in the cytoplasm. This mechanism is catalyzed by a complex machinery known as the spliceosome, which is conformed by more than 300 proteins and ribonucleoproteins that activate and regulate the precision of gene expression when assembled. It has been proposed that several genetic diseases are related to defects in the splicing process, including cancer. For this reason, natural products that show the ability to regulate splicing have attracted enormous attention due to its potential use for cancer treatment. Some microbial metabolites have shown the ability to inhibit gene splicing and the molecular mechanism responsible for this inhibition is being studied for future applications. Here, we summarize the main types of natural products that have been characterized as splicing inhibitors, the recent advances regarding molecular and cellular effects related to these molecules, and the applications reported so far in cancer therapeutics.

circRNA-UBAP2 promotes the proliferation and inhibits apoptosis of ovarian cancer though miR-382-5p/PRPF8 axis

“…It was reported that the events of splicing were related to tumor progression, the alternative splicing of different pre-mRNAs is altered during oncogenic progression with the concomitant development of cancer features, like an increase in vascularization, cell proliferation, and invasion [24].…”

Alternative splicing: the pledge, the turn, and the prestige

“…This technique made it indeed possible to enhance the correction of ATM aberrant splicing causing ataxia-telangiectasia, a recessive neurogenetic disorder, by being able to deliver the ASO to the brain and cerebellum (Du et al 2011 ). Delivery limitations have also promoted the discovery of small molecule modulators of splicing (Salton and Misteli 2016 ), identified as a good spliceosome-targeting tool and that can be synthetic or derived from natural products as fungi, medicinal plants and bacteria (Martínez-Montiel et al 2016 ). For instance, the spliceosome SF3b subunit has been shown to be targeted by three bacterial natural products, pladienolide, herboxidiene and the FR901464 molecule, as well as by meaymicin, a synthetic analogue of FR901464 (Albert et al 2009 ; Webb et al 2013 ).…”

Alternative Splicing in Breast Cancer and the Potential Development of Therapeutic Tools

“…Diverse combinations of splicing events could generate different mature mRNAs that could in turn produce distinct protein products due to alternative splicing (AS). AS is the main source of protein diversity involved in 90% of human gene expression [ 51 , 52 ], which has recently become a hallmark for cancer [ 53 ] and the target for the development of new therapeutic molecules [ 54 , 55 ]. In the past few years, genomic information related to different types of cancer has been annotated in several databases, including The Cancer Genome Atlas ( ).…”

“…For example, it has been recently demonstrated that the antidiuretic amiloride has the ability to affect the splicing of several genes while showing anti-tumor activity [ 120 ]. Other small molecules with antitumor activity that block splicing correspond to a collection of microbial metabolites like spliceostatin or pladienolide [ 55 ] and even when the overall outcome for these molecules is the inhibition of cancer-related processes like proliferation and cell cycle, a complete inactivation of splicing could have adverse accessory effects for the organism.…”