Abstract:Post-transcriptional deregulation is a defining feature of metastatic cancer. While many microRNAs have been implicated as regulators of metastatic progression, less is known about the roles and mechanisms of RNA-binding proteins in this process. We identified muscleblind-like 1 (MBNL1), a gene implicated in myotonic dystrophy, as a robust suppressor of multiorgan breast cancer metastasis. MBNL1 binds the 3 ′ untranslated regions (UTRs) of DBNL (drebrin-like protein) and TACC1 (transforming acidic coiled-coil … Show more
“…For examples, microtubule-associated protein tau is associated with paclitaxel resistance in breast and gastric cancer patients [34, 35] and upregulated hepatocyte growth factor activator and trypsin like proteases in cancer tissues are involved with carcinogenesis and metastasis [36]. In contrast, muscleblind-like protein 1 is implicated in suppression of breast cancer metastatic colonization [37]; granzymes play key role in antitumor immunity [38] and FKBP1A is a target for anticancer drug rapamycin [39]. Predicted interaction of our compounds with previously reported proteins in cancer provides evidence for their beneficial role.Fig.…”
BackgroundTributyltin (IV) compounds are promising candidates for drug development. In the current study, we evaluated in-vitro and in-silico profile of carboxylate derivatives of tributyltin (IV) complexes.MethodsADMET and drug-likeliness properties were predicted using MetaPrint2D React, preADMET, SwissADME and Molsoft tools. SwissTargetPrediction predicted molecular targets for compounds. In-vitro bioactivity was evaluated by quantifying cytotoxicity against HepG2, THP-1 cell lines, isolated lymphocytes and leishmania promastigotes as well as measuring protein kinase (PK) inhibition activity.ResultsResults indicate partial compliance of compounds with drug-likeliness rules. Ch-409 complies with WDI and Lipinski rules. ADMET profile prediction shows strong plasma protein binding except for Ch-409, low to high GI absorption and BBB penetration (Cbrain/Cblood = 0.942–11; caco-2 cells permeability 20.13–26.75 nm/sec), potential efflux by P-glycoprotein, metabolism by CYP3A4, medium inhibition of hERG, mutagenicity and capacity to be detoxified by glutathionation and glucuronidation. Molecular targets include proteases, enzymes, membrane receptors, transporters and ion channels where Ch-409 targets membrane receptors only. Compounds are significantly (p < 0.05) cytotoxic against HepG2 cell line and leishmania as compared with normal isolated lymphocytes. Ch-459 indicates highest toxicity against leishmania (mortality 97.9 ± 3.99%; LC50 0.323 ± 0.002 μg/mL) whereas Ch-409 possesses maximum cytotoxicity against HepG2 cell line (IC50 0.08 ± 0.001 μg/mL) as well as 97.5 ± 1.98% (LC50 0.954 ± 0.158 μg/mL) mortality of leishmania promastigotes. It was observed that antileishmanial effect was reduced by 16.38%–34.38% and 15–38.2% in the presence of NaN3 and mannitol respectively. PK inhibition and reactive oxygen species production are possible mechanisms for cytotoxicity.ConclusionsSelected carboxylate derivatives of tributyltin (IV) complexes possess significant antileishmanial and cytotoxic potential. These are promising compounds for the development of antileishmanial and anticancer drugs.
Graphical AbstractCarboxylate derivatives of tributyltin (IV) complexes as anticancer and antileishmanial agents
“…For examples, microtubule-associated protein tau is associated with paclitaxel resistance in breast and gastric cancer patients [34, 35] and upregulated hepatocyte growth factor activator and trypsin like proteases in cancer tissues are involved with carcinogenesis and metastasis [36]. In contrast, muscleblind-like protein 1 is implicated in suppression of breast cancer metastatic colonization [37]; granzymes play key role in antitumor immunity [38] and FKBP1A is a target for anticancer drug rapamycin [39]. Predicted interaction of our compounds with previously reported proteins in cancer provides evidence for their beneficial role.Fig.…”
BackgroundTributyltin (IV) compounds are promising candidates for drug development. In the current study, we evaluated in-vitro and in-silico profile of carboxylate derivatives of tributyltin (IV) complexes.MethodsADMET and drug-likeliness properties were predicted using MetaPrint2D React, preADMET, SwissADME and Molsoft tools. SwissTargetPrediction predicted molecular targets for compounds. In-vitro bioactivity was evaluated by quantifying cytotoxicity against HepG2, THP-1 cell lines, isolated lymphocytes and leishmania promastigotes as well as measuring protein kinase (PK) inhibition activity.ResultsResults indicate partial compliance of compounds with drug-likeliness rules. Ch-409 complies with WDI and Lipinski rules. ADMET profile prediction shows strong plasma protein binding except for Ch-409, low to high GI absorption and BBB penetration (Cbrain/Cblood = 0.942–11; caco-2 cells permeability 20.13–26.75 nm/sec), potential efflux by P-glycoprotein, metabolism by CYP3A4, medium inhibition of hERG, mutagenicity and capacity to be detoxified by glutathionation and glucuronidation. Molecular targets include proteases, enzymes, membrane receptors, transporters and ion channels where Ch-409 targets membrane receptors only. Compounds are significantly (p < 0.05) cytotoxic against HepG2 cell line and leishmania as compared with normal isolated lymphocytes. Ch-459 indicates highest toxicity against leishmania (mortality 97.9 ± 3.99%; LC50 0.323 ± 0.002 μg/mL) whereas Ch-409 possesses maximum cytotoxicity against HepG2 cell line (IC50 0.08 ± 0.001 μg/mL) as well as 97.5 ± 1.98% (LC50 0.954 ± 0.158 μg/mL) mortality of leishmania promastigotes. It was observed that antileishmanial effect was reduced by 16.38%–34.38% and 15–38.2% in the presence of NaN3 and mannitol respectively. PK inhibition and reactive oxygen species production are possible mechanisms for cytotoxicity.ConclusionsSelected carboxylate derivatives of tributyltin (IV) complexes possess significant antileishmanial and cytotoxic potential. These are promising compounds for the development of antileishmanial and anticancer drugs.
Graphical AbstractCarboxylate derivatives of tributyltin (IV) complexes as anticancer and antileishmanial agents
“…Among splicing factors known to drive developmental splicing transitions in non-erythroid cells, the zinc finger RBPs known as MBNL1 and MBNL2 are leading candidates for performing this role in erythroblasts. Depending on the location of binding, MBNL proteins can regulate splicing, polyadenylation, RNA stability, and RNA localization in several systems [30–36]. Deficits in MBNL function also have disease relevance.…”
Section: Regulation Of the Erythroid Splicing Programmentioning
Purpose of review
Erythroid progenitors must accurately and efficiently splice thousands of pre-mRNAs as the cells undergo extensive changes in gene expression and cellular remodeling during terminal erythropoiesis. Alternative splicing choices are governed by interactions between RNA binding proteins (RBPs) and cis-regulatory binding motifs in the RNA. This review will focus on recent studies that define the genome-wide scope of splicing in erythroblasts and discuss what is known about its regulation.
Recent findings
RNA-seq analysis of highly purified erythroblast populations has revealed an extensive program of alternative splicing of both exons and introns. During normal erythropoiesis, stage-specific splicing transitions alter the structure and abundance of protein isoforms required for optimized red cell production. Mutation or deficiency of splicing regulators underlies hematopoietic disease in myelopdysplasia syndrome (MDS) patients via disrupting the splicing program.
Summary
Erythroid progenitors execute an elaborate alternative splicing program that modulates gene expression post-transcriptionally, ultimately regulating the structure and function of the proteome in a differentiation stage-specific manner during terminal erythropoiesis. This program helps drives differentiation and ensures synthesis of the proper protein isoforms required to produce mechanically stable red cells. Mutation or deficiency of key splicing regulatory proteins disrupts the splicing program to cause disease.
“…Accumulating evidence suggests that MBNL proteins play critical roles in tumorigenesis 17 . It has been shown that MBNL1 suppresses breast cancer metastatic colonization through regulating transcript stabilization 18 . A recent study showed that MBNL1 inhibited colorectal cancer metastasis by modulation of the Snail/E-cadherin axis 19 .…”
Tumor metastasis is the predominant cause of lethality in cancer. We found that Neobractatin (NBT), a natural compound isolated from Garcinia bracteata, could efficiently inhibit breast and lung cancer cells metastasis. However, the mechanisms of NBT inhibiting cancer metastasis remain unclear. Based on the RNA-sequencing result and transcriptome analysis, Muscleblind-like 2 (MBNL2) was found to be significantly upregulated in the cells treated with NBT. The Cancer Genome Atlas (TCGA) database analysis indicated that the expression of MBNL2 in breast and lung carcinoma tumor tissues was significantly lower compared to normal tissues. We thus conducted to investigate the antimetastatic role of MBNL2. MBNL2 overexpression mimicked the effect of NBT on breast cancer and lung cancer cell motility and metastasis, in addition significantly enhanced the inhibition effect of NBT. MBNL2 knockdown furthermore partially eliminated the inhibitory effect of NBT on metastasis. Mechanistically, we demonstrated that NBT-and MBNL2mediated antimetastasis regulation significantly correlated with the pAKT/epithelial-mesenchymal transition (EMT) pathway. Subsequent in vivo study showed the same metastasis inhibition effect in NBT and MBNL2 in MDA-MB-231 xenografts mouse model. This study suggest that NBT possesses significant antitumor activity in breast and lung cancer cells that is partly mediated through the MBNL2 expression and enhancement in metastasis via the pAKT/EMT signaling pathway.
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