Norcycloartocarpin targets Akt and suppresses Akt-dependent survival and epithelial-mesenchymal transition in lung cancer cells

Nonpanya, Nongyao; Sanookpan, Kittipong; Joyjamras, Keerati; Wichadakul, Duangdao; Sritularak, Boonchoo; Chaotham, Chatchai; Chanvorachote, Pithi

doi:10.1371/journal.pone.0254929

Cited by 4 publications

(3 citation statements)

References 95 publications

(89 reference statements)

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“…A polyphenol compound, PE5, efficiently suppresses Akt/mTOR, and Bcl-2 induces autophagic cell death in NSCLC [ 47 ]. Norcycloartocarpin targeting Akt suppresses cancer cell motility by suppressing the epithelial-mesenchymal transition [ 48 ]. Recently, the inhibitor of Akt was shown to have a potential for cancer stem cell inhibition [ 49 ].…”

Section: Discussionmentioning

confidence: 99%

N,Nʹ-Diarylurea Derivatives (CTPPU) Inhibited NSCLC Cell Growth and Induced Cell Cycle Arrest through Akt/GSK-3β/c-Myc Signaling Pathway

Thongsom

Racha

Zin

et al. 2023

IJMS

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Lung cancer is one of the most common malignancies worldwide. Non-small-cell lung cancer (NSCLC) accounts for more than 80% of lung cancers, shows chemotherapy resistance, metastasis, and relapse. The phosphatidylinositol-3 kinase (PI3K)/Akt pathway has been implicated in the carcinogenesis and disease progression of NSCLC, suggesting that it may be a promising therapeutic target for cancer therapy. Although phenylurea derivatives have been reported as potent multiple kinase inhibitors, novel unsymmetrical N,Nʹ-diarylurea derivatives targeting the PI3K/Akt pathway in NSCLC cells remain unknown. Methods: N,Nʹ-substituted phenylurea derivatives CTPPU and CT-(4-OH)-PU were investigated for their anticancer proliferative activity against three NSCLC cell lines (H460, A549, and H292) by 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide, colony formation, Hoechst33342/PI staining assays, and apoptosis analysis. The protein expressions of Akt pathway-related proteins in response to CTPPU or CT-(4-OH)-PU were detected by Western blot analysis. The Kyoto Encyclopedia of Genes and Genomes mapper was used to identify the possible signaling pathways in NSCLC treated with CTPPU. The cell cycle was analyzed by flow cytometry. Molecular docking was used to investigate the possible binding interaction of CTPPU with Akt, the mammalian target of rapamycin complex 2 (mTORC2), and PI3Ks. Immunofluorescence and Western blot analysis were used to validate our prediction. Results: The cytotoxicity of CTPPU was two-fold higher than that of CT-(4-OH)-PU for all NSCLC cell lines. Similarly, the non-cytotoxic concentration of CTPPU (25 µM) dramatically inhibited the colony formation of NSCLC cells, whereas its relative analog CT-(4-OH)-PU had no effect. Protein analysis revealed that Akt and its downstream effectors, namely, phosphorylated glycogen synthase kinase (GSK)-3β (Ser9), β-catenin, and c-Myc, were reduced in response to CTPPU treatment, which suggested the targeting of Akt-dependent pathway, whereas CT-(4-OH)-PU had no effect on such cell growth regulatory signals. CTPPU induced G1/S cell cycle arrest in lung cancer cells. Immunofluorescence revealed that CTPPU decreased p-Akt and total Akt protein levels, which implied the effect of the compound on protein activity and stability. Next, we utilized in silico molecular docking analysis to reveal the potential molecular targets of CTPPU, and the results showed that the compound could specifically bind to the allosteric pocket of Akt and three sites of mTORC2 (catalytic site, A-site, and I-site), with a binding affinity greater than that of reference compounds. The compound cannot bind to PI3K, an upstream regulator of the Akt pathway. The effect of CTPPU on PI3K and Akt was confirmed. This finding indicated that the compound could decrease p-Akt but caused no effect on p-PI3K. Conclusions: The results indicate that CTPPU significantly inhibits NSCLC cell proliferation by inducing G1/S cell cycle arrest via the Akt/GSK-3β/c-Myc signaling pathway. Molecular docking revealed that CTPPU could interact with Akt and mTORC2 molecules with a high binding affinity. These data indicate that CTPPU is a potential novel alternative therapeutic approach for NSCLC.

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Section: Discussionmentioning

confidence: 99%

N,Nʹ-Diarylurea Derivatives (CTPPU) Inhibited NSCLC Cell Growth and Induced Cell Cycle Arrest through Akt/GSK-3β/c-Myc Signaling Pathway

Thongsom

Racha

Zin

et al. 2023

IJMS

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“…Recently, it was shown that compounds isolated from Artocarpus gomezianus , the Thai medicinal plant, have promising antimetastatic activity in human lung cancer cells [ 32 , 33 , 34 ]. Here, we have revealed novel information about the effect of the new active compound, cycloartocarpin ( Figure 1 A), extracted from A. gomezianus , on EMT and cell migration.…”

Section: Discussionmentioning

confidence: 99%

Cycloartocarpin Inhibits Migration through the Suppression of Epithelial-to-Mesenchymal Transition and FAK/AKT Signaling in Non-Small-Cell Lung Cancer Cells

2022

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Lung cancer metastasis is a multifaceted process that accounts for 90% of cancer deaths. According to several studies, the epithelial–mesenchymal transition (EMT) plays an essential role in lung cancer metastasis. Therefore, this study aimed to investigate the potential pharmacological effect of cycloartocarpin on the suppression of metastasis-related behaviors and EMT. An MTT assay was used to examine cell viability. Cell migration was determined using a wound healing assay. Anchorage-independent cell growth was also performed. Western blot analysis was used to identify the key signaling proteins involved in the regulation of EMT and migration. The results found that non-toxic concentrations of cycloartocarpin (10–20 μM) effectively suppressed cell migration and attenuated anchorage-independent growth in H292, A549, and H460 cells. Interestingly, these effects were consistent with the findings of Western blot analysis, which revealed that the level of phosphorylated focal adhesion kinase (p-FAK), phosphorylated ATP-dependent tyrosine kinase (p-AKT), and cell division cycle 42 (Cdc42) were significantly reduced, resulting in the inhibition of the EMT process, as evidenced by decreased N-cadherin, vimentin, and slug expression. Taken together, the results suggest that cycloartocarpin inhibits EMT by suppressing the FAK/AKT signaling pathway, which is involved in Cdc42 attenuation. Our findings demonstrated that cycloartocarpin has antimetastatic potential for further research and development in lung cancer therapy.

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“…Formins are responsible for the linear polymerisation of F-actin in filopodia while fascin cross-links the formed filaments in parallel bundles [ 68 , 69 ]. Formation of filopodia [ 70 , 71 ] downstream of activation of TWIST1 and SNAIL1 [ 72 ] and the expression of formins [ 73 , 74 ] regulate the migration of cancer cells undergoing EMT. Additionally, the upregulation of formins contributes to metastasis formation [ 75 ], and high levels of fascin correlate with poor prognosis in a number of cancers including breast, lung, gastrointestinal and oral squamous cell carcinoma [ 64 , 76 , 77 ], suggesting that their role in EMT contributes to cell invasion and the formation of secondary tumour foci.…”

Section: Invasive Adhesions Formed By Cells Undergoing Emt In Solid T...mentioning

confidence: 99%

Epithelial Mesenchymal Transition (EMT) and Associated Invasive Adhesions in Solid and Haematological Tumours

Greaves

Calle

2022

Cells

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In solid tumours, cancer cells that undergo epithelial mesenchymal transition (EMT) express characteristic gene expression signatures that promote invasive migration as well as the development of stemness, immunosuppression and drug/radiotherapy resistance, contributing to the formation of currently untreatable metastatic tumours. The cancer traits associated with EMT can be controlled by the signalling nodes at characteristic adhesion sites (focal contacts, invadopodia and microtentacles) where the regulation of cell migration, cell cycle progression and pro-survival signalling converge. In haematological tumours, ample evidence accumulated during the last decade indicates that the development of an EMT-like phenotype is indicative of poor disease prognosis. However, this EMT phenotype has not been directly linked to the assembly of specific forms of adhesions. In the current review we discuss the role of EMT in haematological malignancies and examine its possible link with the progression towards more invasive and aggressive forms of these tumours. We also review the known types of adhesions formed by haematological malignancies and speculate on their possible connection with the EMT phenotype. We postulate that understanding the architecture and regulation of EMT-related adhesions will lead to the discovery of new therapeutic interventions to overcome disease progression and resistance to therapies.

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Norcycloartocarpin targets Akt and suppresses Akt-dependent survival and epithelial-mesenchymal transition in lung cancer cells

Cited by 4 publications

References 95 publications

N,Nʹ-Diarylurea Derivatives (CTPPU) Inhibited NSCLC Cell Growth and Induced Cell Cycle Arrest through Akt/GSK-3β/c-Myc Signaling Pathway

N,Nʹ-Diarylurea Derivatives (CTPPU) Inhibited NSCLC Cell Growth and Induced Cell Cycle Arrest through Akt/GSK-3β/c-Myc Signaling Pathway

Cycloartocarpin Inhibits Migration through the Suppression of Epithelial-to-Mesenchymal Transition and FAK/AKT Signaling in Non-Small-Cell Lung Cancer Cells

Epithelial Mesenchymal Transition (EMT) and Associated Invasive Adhesions in Solid and Haematological Tumours

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