Nimbolide reduces CD44 positive cell population and induces mitochondrial apoptosis in pancreatic cancer cells

Kumar, Sandeep; Inigo, Joseph R.; Kumar, Rahul; Chaudhary, Ajay Kumar; O’Malley, Jordan; Balachandar, Srimmitha; Wang, Jianmin; Attwood, Kristopher; Yadav, Neelu; Hochwald, Steven N.; Wang, Xinjiang; Chandra, Dhyan

doi:10.1016/j.canlet.2017.10.029

Cited by 26 publications

(21 citation statements)

References 84 publications

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“…Consistent with our results, Kumar et al reported that CD44 was overexpressed and contributed to poor 5-year OS rate in pancreatic cancer patients. 21 Furthermore, CD44 expression was notably high and associated with dismal clinical outcomes in cancers including non-small-cell lung cancer, 22 breast cancer, 16 oral squamous cell carcinoma, 23 ovarian cancer 24 and gastric cancer. 25 All these findings suggested that CD44 could be a biomarker for early diagnosis or prognosis prediction of GBC.…”

Section: Discussionmentioning

confidence: 99%

CD44 is overexpressed and correlated with tumor progression in gallbladder cancer

Xue

et al. 2018

CMAR

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BackgroundGallbladder cancer (GBC) is a highly lethal disease and the most common biliary tract malignant tumor with poor prognosis. Accumulating evidence indicates that cluster of differentiation 44 (CD44) is overexpressed in several malignancies and has a crucial role in the development of cancer. However, its expression and function in GBC are unclear. The aim of this study was to explore CD44 expression and its role in GBC.Materials and methodsThe expression of CD44 was measured by immunohistochemistry. Tissue microarray analysis was used to confirm the relationship between CD44 expression and clinical outcomes of GBC patients. EDU assay, colony formation assay, cell migration and invasion assay were performed to detect the functions of CD44 in GBC-SD and NOZ transfected with si-RNA.ResultsCD44 was overexpressed and associated with poor outcomes in GBC patients. The univariate and multivariate analyses confirmed that elevated CD44 was an independent prognostic factor for the OS of GBC patients. Silencing CD44 could suppress the GBC cell proliferation, migration and invasion in vitro, as well as attenuated cancer stem cell functions.ConclusionCD44 markedly correlated with aggressive tumor behaviors and contributed to the progression of GBC, which could represent a novel prognostic marker and potential therapeutic target for GBC patients.

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Section: Discussionmentioning

confidence: 99%

CD44 is overexpressed and correlated with tumor progression in gallbladder cancer

Xue

et al. 2018

CMAR

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“…An overwhelming body of evidence indicates that nimbolide inhibits the proliferation of cancer cells by inducing apoptosis 11 – 13 , 19 – 26 . Nimbolide has been reported to transduce apoptosis by modulating signalling networks that regulate both the intrinsic and extrinsic pathways of apoptotic cell death 13 , 15 , 25 , 26 .…”

Section: Introductionmentioning

confidence: 99%

Nimbolide, a neem limonoid inhibits cytoprotective autophagy to activate apoptosis via modulation of the PI3K/Akt/GSK-3β signalling pathway in oral cancer

et al. 2018

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Of late, nimbolide, a limonoid from the neem tree (Azadirachta indica) has gained increasing research attention owing to its potent antiproliferative and apoptosis-inducing effects. The present study was designed to investigate the effect of nimbolide on autophagy and the time point at which the phosphorylation status of GSK-3β and PI3K dictate the choice between autophagy and apoptosis in SCC131 and SCC4 oral cancer cells. Additionally, we analysed changes in the expression of proteins involved in autophagy and apoptosis after therapeutic intervention with nimbolide in a hamster model of oral oncogenesis. Furthermore, we also demonstrate changes in the expression of key genes involved in apoptosis and autophagy during the stepwise evolution of hamster and human OSCCs. Nimbolide-induced stereotypical changes in oral cancer cells characteristic of both apoptosis and autophagy. Time-course experiments revealed that nimbolide induces autophagy as an early event and then switches over to apoptosis. Nimbolide negatively regulates PI3K/Akt signalling with consequent increase in p-GSK-3βTyr216, the active form of GSK-3β that inhibits autophagy. Downregulation of HOTAIR, a competing endogenous RNA that sponges miR-126 may be a major contributor to the inactivation of PI3K/Akt/GSK3 signalling by nimbolide. Analysis of key markers of apoptosis and autophagy as well as p-AktSer473 during sequential progression of hamster and human OSCC revealed a gradual evolution to a pro-autophagic and antiapoptotic phenotype that could confer a survival advantage to tumors. In summary, the results of the present study provide insights into the molecular mechanisms by which nimbolide augments apoptosis by overcoming the shielding effects of cytoprotective autophagy through modulation of the phosphorylation status of Akt and GSK-3β as well as the ncRNAs miR-126 and HOTAIR. Development of phytochemicals such as nimbolide that target the complex interaction between proteins and ncRNAs that regulate the autophagy/apoptosis flux is of paramount importance in cancer prevention and therapeutics.

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“…The GO and KEGG enrichment analyses suggest that these DEmRNAs have a significant effect on tumor-associated biological functions. Among the 12 total pathways, 'focal adhesion', 'ECM-receptor interaction', 'microRNAs in cancer' and 'proteoglycans in cancer' are associated with the progression of PDAC (45)(46)(47)(48). The PPI network was established, including the six hubgenes (THBS1, FN1, TGFB2, ITGA1, ITGA3, and TIMP3), to further identify the key circRNAs participating in the regulatory network.…”

Section: Discussionmentioning

confidence: 99%

Integrated analysis of circular RNA‑associated ceRNA network in pancreatic ductal adenocarcinoma

Song

Wang

et al. 2020

Oncol Lett

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Circular RNAs (circRNAs) have displayed dysregulated expression in several types of cancer. However, the functions of the majority of circRNAs in pancreatic ductal adenocarcinoma (PDAC) remain unknown. The present study aimed to investigate the expression, functions and molecular mechanisms of circRNAs in PDAC. The circRNAs, mRNAs and the microRNA (miRNAs) expression profiles were obtained from three Gene Expression Omnibus microarray datasets, and a circRNA-miRNA-mRNA and circRNA-miRNA-hubgene network was established. The interactions between proteins were analyzed using the Search Tool for the Retrieval of Interacting Genes/Proteins database, and hubgenes were identified using the MCODE plugin. A total of eight differentially expressed circRNAs (DEcircRNAs), 44 differentially expressed miRNAs (DEmiRNAs), and 2,052 differ entially expressed mRNAs (DEmRNAs) were identified. The present study successfully constructed a circRNA-miRNA-mRNA competing endogenous RNA (ceRNA) network based on four circRNAs, six miRNAs and 111 mRNAs in PDAC. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathways analyses indicated that DEmRNAs may participate in the pathogenesis and progression of PDAC. The protein-protein interaction network and module analysis identified six hubgenes (THBS1, FN1, TIMP3, TGFB2, ITGA1 and ITGA3). Furthermore, the circRNA-miRNA-hubgene regulatory modules were constructed based on the three DEcircRNAs, one DEmiRNAs and five DEmRNAs. In conclusion, the results of the present study improve the current understanding of the pathogenesis of PDAC.

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Nimbolide reduces CD44 positive cell population and induces mitochondrial apoptosis in pancreatic cancer cells

Cited by 26 publications

References 84 publications

CD44 is overexpressed and correlated with tumor progression in gallbladder cancer

CD44 is overexpressed and correlated with tumor progression in gallbladder cancer

Nimbolide, a neem limonoid inhibits cytoprotective autophagy to activate apoptosis via modulation of the PI3K/Akt/GSK-3β signalling pathway in oral cancer

Integrated analysis of circular RNA‑associated ceRNA network in pancreatic ductal adenocarcinoma

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