Dictamnine, a novel c-Met inhibitor, suppresses the proliferation of lung cancer cells by downregulating the PI3K/AKT/mTOR and MAPK signaling pathways

Yu, Jiaojiao; Zhang, Lijing; Peng, Jun; Ward, Richard J.; Hao, Peiqi; Wang, Jiwei; Zhang, Na; Yang, Yang; Guo, Xuewu; Cheng, Xiang; An, Su; Xu, Tian‐Rui

doi:10.1016/j.bcp.2021.114864

Cited by 32 publications

(17 citation statements)

References 53 publications

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“…The nuclear translocation of β-catenin enhances the transcriptional activity and subsequent events associated with tumorigenesis [46,47]. Yu and colleagues made a similar observation in the downregulation of all these pathways upon treatment with dictamnine (c-Met inhibitor) in lung cancer cells [48]. Further, we were interested to learn about the effect of forced expression of MnSOD by transfecting colon cancer cells with pcDNA3-MnSOD.…”

Section: Discussionmentioning

confidence: 91%

2,3,5,6-Tetramethylpyrazine Targets Epithelial-Mesenchymal Transition by Abrogating Manganese Superoxide Dismutase Expression and TGFβ-Driven Signaling Cascades in Colon Cancer Cells

et al. 2022

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Epithelial-mesenchymal transition (EMT) is a crucial process in which the polarized epithelial cells acquire the properties of mesenchymal cells and gain invasive properties. We have previously demonstrated that manganese superoxide dismutase (MnSOD) can regulate the EMT phenotype by modulating the intracellular reactive oxygen species. In this report, we have demonstrated the EMT-suppressive effects of 2,3,5,6-Tetramethylpyrazine (TMP, an alkaloid isolated from Chuanxiong) in colon cancer cells. TMP suppressed the expression of MnSOD, fibronectin, vimentin, MMP-9, and N-cadherin with a parallel elevation of occludin and E-cadherin in unstimulated and TGFβ-stimulated cells. Functionally, TMP treatment reduced the proliferation, migration, and invasion of colon cancer cells. TMP treatment also modulated constitutive activated as well as TGFβ-stimulated PI3K/Akt/mTOR, Wnt/GSK3/β-catenin, and MAPK signaling pathways. TMP also inhibited the EMT program in the colon cancer cells-transfected with pcDNA3-MnSOD through modulation of MnSOD, EMT-related proteins, and oncogenic pathways. Overall, these data indicated that TMP may inhibit the EMT program through MnSOD-mediated abrogation of multiple signaling events in colon cancer cells.

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Section: Discussionmentioning

confidence: 91%

2,3,5,6-Tetramethylpyrazine Targets Epithelial-Mesenchymal Transition by Abrogating Manganese Superoxide Dismutase Expression and TGFβ-Driven Signaling Cascades in Colon Cancer Cells

et al. 2022

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“…Importantly, we further identified tNOX as the protein target of these heteroarene-fused anthraquinones. CETSA, which has recently emerged as a powerful tool for clarifying the binding affinity of drugs to their intracellular protein targets, can be used to identify potent and selective compounds that may serve as potential therapeutic agents in an array of applications [55][56][57]. Here, we used CETSA and molecular docking simulations to identify and validate tNOX as a key protein target of these novel heteroarene-fused anthraquinones, and we propose that this targeting elicits their anticancer properties.…”

Section: Discussionmentioning

confidence: 99%

Bis(chloroacetamidino)-Derived Heteroarene-Fused Anthraquinones Bind to and Cause Proteasomal Degradation of tNOX, Leading to c-Flip Downregulation and Apoptosis in Oral Cancer Cells

Chang

Chen

Тихомиров

et al. 2022

Cancers

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Anthraquinone-based intercalating compounds, namely doxorubicin and mitoxantrone, have been used clinically based on their capacity to bind DNA and induce DNA damage. However, their applications have been limited by side effects and drug resistance. New-generation anthraquinone derivatives fused with different heterocycles have been chemically synthesized and screened for higher anticancer potency. Among the compounds reported in our previous study, 4,11-bis(2-(2-chloroacetamidine)ethylamino)anthra[2,3-b]thiophene-5,10-dione dihydrochloride (designated 2c) was found to be apoptotic, but the direct cellular target responsible for the cytotoxicity remained unknown. Here, we report the synthesis and anticancer properties of two other derivatives, 4,11-bis(2-(2-chloroacetamidine)ethylamino)naphtho[2,3-f]indole-5,10-dione dihydrochloride (2a) and 4,11-bis(2-(2-chloroacetamidine)ethylamino)-2-methylanthra[2,3-b]furan-5,10-dione dihydrochloride (2b). We sought to identify and validate the protein target(s) of these derivatives in oral cancer cells, using molecular docking simulations and cellular thermal shift assays (CETSA). Our CETSA results illustrate that these derivatives targeted the tumor-associated NADH oxidase (tNOX, ENOX2), and their direct binding downregulated tNOX in p53-functional SAS and p53-mutated HSC-3 cells. Interestingly, the compounds targeted and downregulated tNOX to reduce SIRT1 deacetylase activity and increase Ku70 acetylation, which triggers c-Flip ubiquitination and induces apoptosis in oral cancer cells. Together, our data highlight the potential value of these heteroarene-fused anthraquinones in managing cancer by targeting tNOX and augmenting apoptosis.

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“…New research reveals that the phosphatidlinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway plays a key role in cancer cell proliferation, tumorigenesis and metastasis, 14 apoptosis, glucose metabolism, and DNA repair. 15 Based on the importance of this pathway, many potential drugs 16,17 and natural products 18,19 are being studied targeting the PI3K/AKT/mTOR pathway for cancer treatment through inhibiting cell growth or inducing apoptosis as well as ferroptosis. 20 Li et al 21 showed that activation of the PI3K/AKT/mTOR pathway promotes a shift in small cell lung cancer (SCLC) phenotype, which in turn confers resistance to chemotherapy in SCLC cells.…”

Section: Introductionmentioning

confidence: 99%

Single‐cell RNA sequencing reveals the mechanism of PI3K/AKT/mTOR signaling pathway activation in lung adenocarcinoma by KRAS mutation

Xu,

Ding,

Song

et al. 2024

The Journal of Gene Medicine

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BackgroundAberrant activation of the phosphatidlinositol 3‐kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway has been shown to play an important role in lung adenocarcinoma (LUAD). The effect of KRAS mutations, one of the important signatures of LUAD, on the PI3K/AKT/mTOR pathway in LUAD remains unclear.MethodsThe Seurat package and principal component analysis were used for cell categorization of single‐cell RNA sequencing data of LUAD. The AUCell score was used to assess the activity of the PI3K/AKT/mTOR pathway. Meanwhile, using the gene expression profiles and mutation profiles in the The Cancer Genome Atlas dataset, LUAD patients were categorized into KRAS‐mutant (KRAS‐MT) and KRAS‐wild‐types (KRAS‐WT), and the corresponding enrichment scores were calculated using gene set enrichment analysis analysis. Finally, the subpopulation of cells with the highest pathway activity was identified, the copy number variation profile of this subpopulation was inscribed using the inferCNV package and the CMap database was utilized to make predictions for drugs targeting this subpopulation.ResultsThere is higher PI3K/AKT/mTOR pathway activity in LUAD epithelial cells with KRAS mutations, and high expression of KRAS, PIK3CA, AKT1 and PDPK1. In particular, we found significantly higher levels of pathway activity and associated gene expression in KRAS‐MT than in KRAS‐WT. We identified the highest pathway activity on a subpopulation of GRB2+ epithelial cells and the presence of amplified genes within its pathway. Finally, drugs were able to target GRB2+ epithelial cell subpopulations, such as wortmannin, palbociclib and angiogenesis inhibitor.ConclusionsThe present study provides a basic theory for the activation of the PI3K/AKT/mTOR signaling pathway as a result of KRAS mutations.

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Dictamnine, a novel c-Met inhibitor, suppresses the proliferation of lung cancer cells by downregulating the PI3K/AKT/mTOR and MAPK signaling pathways

Cited by 32 publications

References 53 publications

2,3,5,6-Tetramethylpyrazine Targets Epithelial-Mesenchymal Transition by Abrogating Manganese Superoxide Dismutase Expression and TGFβ-Driven Signaling Cascades in Colon Cancer Cells

2,3,5,6-Tetramethylpyrazine Targets Epithelial-Mesenchymal Transition by Abrogating Manganese Superoxide Dismutase Expression and TGFβ-Driven Signaling Cascades in Colon Cancer Cells

Bis(chloroacetamidino)-Derived Heteroarene-Fused Anthraquinones Bind to and Cause Proteasomal Degradation of tNOX, Leading to c-Flip Downregulation and Apoptosis in Oral Cancer Cells

Single‐cell RNA sequencing reveals the mechanism of PI3K/AKT/mTOR signaling pathway activation in lung adenocarcinoma by KRAS mutation

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