Blockage of epithelial to mesenchymal transition and upregulation of let 7b are critically involved in ursolic acid induced apoptosis in malignant mesothelioma cell

Abstract

Malignant pleural mesothelioma (MPN), which is caused by asbestos exposure, is one of aggressive lung tumors. In the present study, we elucidated the anti-tumor mechanism of ursolic acid in malignant mesotheliomas. Ursolic acid significantly exerted cytotoxicity in a time and dose dependent manner in H28, H2452 and MSTO-211H mesothelioma cells and inhibited cell proliferation by colony formation assay in a dose-dependent fashion. Also, ursolic acid treatment accumulated the sub-G1 population, attenuated the expression of procapase 9, cyclin D1, pAKT, p-glycogen synthase kinase 3-alpha/beta (pGSK3α/β), β-catenin and nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB) and also cleaved caspase 3 and poly (ADP-ribose) polymerase (PARP) in mesothelioma cells. Furthermore, ursolic acid treatment blocked epithelial and mesenchymal transition (EMT) molecules by activating E-cadherin as an epithelial marker and attenuating Vimentin, and Twist as mesenchymal molecules. Interestingly, miRNA array revealed that 23 miRNAs (>2 folds) including let-7b and miRNA3613-5p, miRNA134 and miRNA196b were significantly upregulated while 33 miRNAs were downregulated in ursolic acid treated H2452 cells. Furthermore, overexpression of let 7b using let-7b mimics enhanced the antitumor effect of ursolic acid to attenuate the expression of procaspases 3, pro-PARP, pAKT, β-catenin and Twist and increase sub-G1 accumulation in H2452 mesothelioma cells. Overall, our findings suggest that ursolic acid induces apoptosis via inhibition of EMT and activation of let7b in mesothelioma cells as a potent chemotherapeutic agent for treatment of malignant mesotheliomas.

<p>Foretinib Inhibits Cancer Stemness and Gastric Cancer Cell Proliferation by Decreasing CD44 and c-MET Signaling</p>

“…62 Other study has reported that suppressed EMT through attenuation of AKT phosphorylation and βcatenin. 63 Our results also indicated that foretinib may suppress β-catenin and AKT phosphorylation through increased ECAD expression. Indeed, foretinib inhibited angiogenesis, Wnt/β-catenin signaling, and the PI3K/Akt pathway in this study by inhibiting VEGFA, HIF-1α, c-MET, and AKT phosphorylation, as well as CCND1, c-MYC, and β-catenin in c-MET-positive GC.…”

Overexpression of miR‐199/214 is a distinctive feature of iron‐induced and asbestos‐induced sarcomatoid mesothelioma in rats

“…The expression of Twist1 was decreased after the transfection of let‐7b mimics in MM cell lines 41 . Overexpression of let‐7 suppressed the production of interleukin‐6 and vascular endothelial growth factor, as well as colony formation in soft agar, in mammary gland epithelium (MCF‐10A) 42 and lung adenocarcinoma (A549) 43 .…”

Complex Determinants of Epithelial: Mesenchymal Phenotypic Plasticity in Ovarian Cancer

“…A recent analysis of serum-circulating exosomal microRNAs revealed a broad increase in miR-373 and miR-200a in patients with ovarian serous adenocarcinoma across all stages (I-IV), while miR-200b and miR200c were more significantly elevated in later stages (III-IV) and correlated with worse survival outcome, suggesting that these microRNAs may differentially modulate EMT/MET shifts during certain EOC progression steps [ 208 ]. Another study [ 209 ] evaluating 2222 total microRNAs from ovarian cancer patient serum samples identified the most stably and markedly downregulated microRNAs as miR-132, miR-26a, and miR-145 (which are known to act as EMT-repressors in other tissue types, as discussed above), as well as let-7b, a microRNA that was recently shown to play multiple anti-tumor roles, including anti-EMT (through attenuation of p-AKT, Twist and β-catenin) and pro-apoptosis in malignant mesothelioma cells [ 210 ]. A 1,170 patient-based meta-analysis of global transcriptome data delineated let-7b as a stratification factor for molecular and clinical classification, and a predictor of poor survival outcome in high grade serous ovarian carcinoma [ 211 ].…”