Multilevel regulation and molecular mechanism of poly (rC)-binding protein 1 in cancer.

Poly (rC)-binding protein 1 (PCBP1), an RNA- or DNA-binding protein with a relative molecular weight of 38 kDa, which is characterized by downregulation in many cancer types. Numerous cases have indicated that PCBP1 could be considered as a tumor suppressor to inhibit tumorigenesis, development, and metastasis. In the current review, we described the multilevel regulatory roles of PCBP1, including gene transcription, alternative splicing, and translation of many cancer-related genes. Additionally, we also provided a brief overview about the inhibitory effect of PCBP1 on most common tumors. More importantly, we summarized the current research status about PCBP1 in hypoxic microenvironment, autophagy, apoptosis, and chemotherapy of cancer cells, aiming to clarify the molecular mechanisms of PCBP1 in cancer. Taken together, in-depth study of PCBP1 in cancer may provide new ideas for cancer therapy.

Crosstalk of the Caspase Family and Mammalian Target of Rapamycin Signaling.

Cell can integrate the caspase family and mammalian target of rapamycin (mTOR) signaling in response to cellular stress triggered by environment. It is necessary here to elucidate the direct response and interaction mechanism between the two signaling pathways in regulating cell survival and determining cell fate under cellular stress. Members of the caspase family are crucial regulators of inflammation, endoplasmic reticulum stress response and apoptosis. mTOR signaling is known to mediate cell growth, nutrition and metabolism. For instance, over-nutrition can cause the hyperactivation of mTOR signaling, which is associated with diabetes. Nutrition deprivation can inhibit mTOR signaling via SH3 domain-binding protein 4. It is striking that Ras GTPase-activating protein 1 is found to mediate cell survival in a caspase-dependent manner against increasing cellular stress, which describes a new model of apoptosis. The components of mTOR signaling-raptor can be cleaved by caspases to control cell growth. In addition, mTOR is identified to coordinate the defense process of the immune system by suppressing the vitality of caspase-1 or regulating other interferon regulatory factors. The present review discusses the roles of the caspase family or mTOR pathway against cellular stress and generalizes their interplay mechanism in cell fate determination.

Transforming growth factor ß signaling pathway: A promising therapeutic target for cancer.

Transforming growth factor ß (TGF-ß) is part of the transforming growth factor ß superfamily which is involved in many physiological processes and closely related to the carcinogenesis. Here, we discuss the TGF-ß structure, function, and its canonical Smads signaling pathway. Importantly, TGF-ß has been proved that it plays both tumor suppressor as well as an activator role in tumor progression. In an early stage, TGF-ß inhibits cell proliferation and is involved in cell apoptosis. In an advanced tumor, TGF-ß signaling pathway induces tumor invasion and metastasis through promoting angiogenesis, epithelial-mesenchymal transition, and immune escape. Furthermore, we are centered on updated research results into the inhibitors as drugs which have been studied in preclinical or clinical trials in tumor carcinogenesis to prevent the TGF-ß synthesis and block its signaling pathways such as antibodies, antisense molecules, and small-molecule tyrosine kinase inhibitors. Thus, it is highlighting the crucial role of TGF-ß in tumor therapy and may provide opportunities for the new antitumor strategies in patients with cancer.

Indisulam exerts anticancer effects via modulation of transcription, translation and alternative splicing on human cervical cancer cells.

Indisulam is a synthetic sulfonamides drug with anticancer activity in various tumors. However, the effect and molecular mechanism of indisulam have still not been studied in human cervical cancer. We treated human cervical cancer cell lines (HeLa and C33A) with indisulam, evaluated its efficacy, and investigated its molecular targets. Indisulam inhibited tumor growth and induced RBM39 degradation in a dose-dependent manner. RNA-seq and proteomics analysis revealed that indisulam disrupted transcriptional regulation pathways related to mRNA splicing and apoptosis. More importantly, indisulam caused mis-splicing of RNA transcripts including p73 isoforms ΔNp73 and TAp73 which have opposite roles in apoptosis regulation. Indisulam increased TAp73 expression and triggered mitochondrial apoptosis independent of p53 status in HeLa cells. In summary, our data suggests that indisulam has therapeutic potential in cervical cancer, representing an attractive strategy in p53-disrupted cancers and should be further investigated.

RNA-binding protein 39: a promising therapeutic target for cancer.

RNA-binding motif protein 39 (RBM39), as a key factor in tumor-targeted mRNA and protein expression, not only plays a vital role in tumorigenesis, but also has broad development prospects in clinical treatment and drug research. Moreover, since RBM39 was identified as a target of sulfonamides, it has played a key role in the emerging field of molecule drug development. Hence, it is of great significance to study the interaction between RBM39 and tumors and the clinical application of drug-targeted therapy. In this paper, we describe the possible multi-level regulation of RBM39, including gene transcription, protein translation, and alternative splicing. Importantly, the molecular function of RBM39 as an important splicing factor in most common tumors is systematically outlined. Furthermore, we briefly introduce RBM39's tumor-targeted drug research and its clinical application, hoping to give reference significance for the molecular mechanism of RBM39 in tumors, and provide reliable ideas for in-depth research for future therapeutic strategies.

Aberrant Bcl-x splicing in cancer: from molecular mechanism to therapeutic modulation.

Bcl-x pre-mRNA splicing serves as a typical example to study the impact of alternative splicing in the modulation of cell death. Dysregulation of Bcl-x apoptotic isoforms caused by precarious equilibrium splicing is implicated in genesis and development of multiple human diseases, especially cancers. Exploring the mechanism of Bcl-x splicing and regulation has provided insight into the development of drugs that could contribute to sensitivity of cancer cells to death. On this basis, we review the multiple splicing patterns and structural characteristics of Bcl-x. Additionally, we outline the cis-regulatory elements, trans-acting factors as well as epigenetic modifications involved in the splicing regulation of Bcl-x. Furthermore, this review highlights aberrant splicing of Bcl-x involved in apoptosis evade, autophagy, metastasis, and therapy resistance of various cancer cells. Last, emphasis is given to the clinical role of targeting Bcl-x splicing correction in human cancer based on the splice-switching oligonucleotides, small molecular modulators and BH3 mimetics. Thus, it is highlighting significance of aberrant splicing isoforms of Bcl-x as targets for cancer therapy.

A SNP involved in alternative splicing of ABCB1 is associated with clopidogrel resistance in coronary heart disease in Chinese population.

Although many scientists are studying the association between genetic polymorphism of ABCB1 and CR in patients, the molecular mechanism has not been further studied in patients with CHD. This study investigated the relationship between SNP of the ABCB1 gene in patients with CHD and CR, and whether the polymorphism of the ABCB1 gene affects the AS of the gene. 741 patients were enrolled in the study, 316 CR cases and 425 NCR cases. The correlation between CR risk and clinical-pathological characteristics were studied. Additionally, the five SNPs were analysed by PCR and Mass Array genotyping methods. Furthermore, silicon analysis was used to predict whether the polymorphism affects the process of AS. Results showed that there was a significant correlation between rs1045642 polymorphism and CR in genotyping and allele analysis. The rs1045642 polymorphism of the ABCB1 gene of CHD patients carrying the A allele are more likely to develop CR. Silicon analysis showed that rs1045642 generated a new ESE sequence which might affect AS of ABCB1 gene. We hypothesize that the mechanism of CR might be caused by a change in the AS caused by the polymorphism of the gene. Thus, this work provides guidance for the clinical use of clopidogrel.

Function, clinical application, and strategies of Pre-mRNA splicing in cancer.

Pre-mRNA splicing is a fundamental process that plays a considerable role in generating protein diversity. Pre-mRNA splicing is also the key to the pathology of numerous diseases, especially cancers. In this review, we discuss how aberrant splicing isoforms precisely regulate three basic functional aspects in cancer: proliferation, metastasis and apoptosis. Importantly, clinical function of aberrant splicing isoforms is also discussed, in particular concerning drug resistance and radiosensitivity. Furthermore, this review discusses emerging strategies how to modulate pathologic aberrant splicing isoforms, which are attractive, novel therapeutic agents in cancer. Last we outline current and future directions of isoforms diagnostic methodologies reported so far in cancer. Thus, it is highlighting significance of aberrant splicing isoforms as markers for cancer and as targets for cancer therapy.

Inhibition of SF3b1 by pladienolide B evokes cycle arrest, apoptosis induction and p73 splicing in human cervical carcinoma cells.

Pladienolide B is a potent cancer cell growth inhibitor that targets the SF3b1 subunit of the spliceosome. There is considerable interest in the compound as a tool to study SF3b1 function in cancer. However, so far little information is available on the molecular mechanism of SF3b1 eliciting apoptosis in cancer cells. Here, we investigated the molecular mechanism of SF3b1 eliciting apoptosis in human cervical carcinoma cells. We demonstrated that inhibition of SF3b1 by pladienolide B inhibited proliferation of HeLa cells at low nanomolar concentrations in a dose- and time-dependent manner. It also induced G2/M phase arrest and significant rise of apoptotic cells. Moreover, it is indicated that inhibition of SF3b1 by pladienolide B induced Tap73/ΔNp73 expression and consequently down-regulated Bax/Bcl-2 ratio, cytochrome c release and caspase-3 expression. Thus, our results showed that SF3b1 plays a pivotal role in cycle arrest, apoptosis induction, and p73 splicing in human cervical carcinoma cells, suggesting that SF3b1 could be used as a potential candidate for cervical cancer therapy.

Exosomes as drug carriers for clinical application.

Exosomes are nanoscale vesicles shed from all cell types and play a major role in communication and transportation of materials between cells due to their ability to transfer proteins and nucleic acids from one cell to another. Analogous in size and function to synthetic nanoparticles, exosomes offer many advantages, rendering them the most promising candidates for targeted drug or gene delivery vehicles. Exosomes can also induce chemoresistance or radioresistance of tumor cells. Studies about the related mechanisms help overcome cancer therapy resistance to some extent. In this review, we focus on the application of exosomes as nanocarriers and the current status of the application of exosomes to cancer therapy.