Pyroptosis is involved in the inhibitory effect of FL118 on growth and metastasis in colorectal cancer.

AIMS: Pyroptosis is a newly discovered inflammatory programmed cell death. This study was to investigate whether pyroptosis is involved in the anti-colorectal cancer process of FL118. MATERIALS AND METHODS: The relationship between NLRP3 and caspase-1 and colorectal cancer was analyzed by bioinformatics. MTT was used to detect the cell viability. Cell membrane integrity was examined by LDH release. Wound healing assay and Transwell were used to detect the cell migration and invasion respectively. TUNEL was to check the cell death. The expression of pyroptosis-related factors was detected using qRT-PCR, Western blotting, Immunofluorescence and Elisa. And H&E staining was used to detect the toxicity of FL118 in colorectal cancer. KEY FINDINGS: In vitro, FL118 significantly inhibited the proliferation, migration and invasion of colorectal cancer, and the morphological characteristics of pyroptosis were observed under the microscope. With the change of FL118 concentration, the release rate of LDH in the supernatant and the expression of pyroptosis-related factors emerged an increase. However, pyroptosis induced by FL118 was reversed with the participation of MCC950 and VX-765, which suppressed the antitumor effect of FL118. In vivo, the result in the xenograft animal model and lung metastasis model experimental showed that FL118 could activate pyroptosis and thus inhibit the metastasis of colorectal cancer. SIGNIFICANCE: FL118 restrains the growth and metastasis of colorectal cancer by inducing NLRP3-ASC-Caspase-1 mediated pyroptosis, which provides important evidence in the study on the role of pyroptosis and different tumors.

Identification of differentially expressed protein-coding genes in lung adenocarcinomas.

Lung adenocarcinoma accounts for a high proportion of lung cancers. Though efforts have been made to develop new and effective treatments for this disease, the mortality rate remains high. Gene expression microarrays facilitate the study of lung cancer at the molecular level. The present study aimed to detect differentially expressed protein-coding genes to identify novel biomarkers and therapeutic targets for lung adenocarcinoma. Aberrations in gene expression in lung adenocarcinoma were determined by analysis of mRNA microarray datasets from the Gene Expression Omnibus database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, protein-protein interaction (PPI) networks and statistical analysis were used to identify the biological functions of the differentially expressed genes (DEGs). The results of the bioinformatics analysis were subsequently validated using reverse transcription-quantitative PCR. A total of 303 DEGs were identified in lung adenocarcinomas, and they were enriched in a number of cancer-associated GO terms and KEGG pathways. DNA topoisomerase 2α (TOP2A), cell division cycle protein homolog 20 (CDC20), mitotic checkpoint serine/threonine protein kinase BUB1 (BUB1) and mitotic spindle assembly checkpoint protein MAD2A (MAD2L1) exhibited the highest degree of interaction in the PPI network. Survival analysis performed using Kaplan-Meier curves and Cox regression indicated that these four genes were all significantly associated with the survival of patients with lung adenocarcinomas. In conclusion, TOP2A, CDC20, BUB1 and MAD2L1 may be key protein-coding genes that may serve as biomarkers and therapeutic targets in lung adenocarcinomas.

Key roles of Rho GTPases, YAP, and Mutant P53 in anti-neoplastic effects of statins.

Emerging epidemiological and preclinical studies have focused on statins and mevalonate pathway to identify potential therapeutic target and clarify the underlying mechanism of the anti-neoplastic effects. Reductions of mevalonate or isoprenoids, caused by statins, would further decrease the isoprenylation of Rho GTPases which is the crucial step for Rho GTPases to anchor on inner cellular membrane. Following anchoring, activated Rho GTPases can mediate a series of cellular activities such as cytoskeleton reprogramming, front-rear polarity, and cell-ECM adhesion. These changes not only facilitate tumor cell detachment and migration but also bring great mechanical changes to directly activate YAP, the major nuclear mechanotransducer, to translocate into nucleus. Recently, statins have been identified as potent inhibitors of YAP. Once entering nucleus, YAP would combine TEADs to promote the transcription of about 100 genes, which are involved in cell proliferation, cell cycle regulation, stemness, invasion, and metastasis. Besides, statins are able to promote the degradation of misfolded mutant p53 (mutp53), which is an oncogene in a variety of human malignancies. Reduction in mevalonate-5-phosphate (MVP), also induced by statins, would impair the stability of DNAJA1-mutp53 complex; then, elevated C terminus of Hsc70-interacting protein (CHIP) mediates the nuclear export and degradation of misfolded mutp53 through ubiquitin-proteasome pathway. It is worth noted that YAP, mutp53, and mevalonate pathway form two positive feedback loops. It is reasonable to believe that Rho GTPases, YAP, and mutp53 are determinants for statins as anti-cancer agents: tumor cells harboring mutp53 and nuclear-located YAP would be more sensitive to statins.

A brief review: some compounds targeting YAP against malignancies.

YAP, acting as a crucial transcription factor in nucleus, regulates the organ size, tissue homeostasis and tumorigenesis. Dysregulation of Hippo-YAP pathway brings a significant impact on the occurrence and development of various tumor types. Moreover, regulation of YAP/TAZ far exceeds the core kinase of the Hippo pathway, and gradually opens up new therapeutic targets. For the moment, chemotherapy together with radiotherapy act as routine methods to prolong the lives of cancer patients. Seeking more effective anti-neoplastic agents seems to be the urgent problem. This brief review focuses on the research progress of YAP inhibitors as the antineoplastic targets. Small molecule inhibitors or drugs have been discovered including verteporfin, dasatinib, statins, A35, JQ1, norcantharidin, agave, MLN8237, dobutamine and peptide-based YAP inhibitors. We are trying to seek novel therapies from the relationship between known drugs and potential mechanisms.