PDK-1 mediated Hippo–YAP–IRS2 signaling pathway and involved in the apoptosis of non-small cell lung cancer cells

Wang, Guofang; Liu, Xiaomei; Xie, Jing; Meng, Jinfei; Ni, Xiaoqin

doi:10.1042/bsr20182099

Cited by 16 publications

(11 citation statements)

References 39 publications

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“…According to observation of the NF1 -related mouse model, nonmyelinating Schwann cells have also been identified 20 , 21 , which implies the vital role of remyelination related to NF1 . For the direct regulation relationship between YAP and NF1, the Hippo-YAP pathway has been demonstrated to be regulated by pyruvate dehydrogenase kinase-1 (PDK-1) 22 , which is involved in the RAS-PI3K-PDK regulation axis 23 . However, no clear evidence exists declaiming this issue.…”

Section: Discussionmentioning

confidence: 99%

Increased nuclear translation of YAP might act as a potential therapeutic target for NF1-related plexiform neurofibroma

Liu¹,

You²,

Tian³

et al. 2021

Int. J. Med. Sci.

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Plexiform neurofibroma (pNF) in the head and neck is a characteristic feature in patients with neurofibromatosis type 1 (NF1) and is associated with significant disfigurement and psychological distress. Yes-associated protein (YAP), the key molecule involved in the Hippo pathway, is a vital transductor that regulates the proliferation and remyelinating of Schwann cells. The functional status of YAP and its feasibility as a potential target are still unknown in pNF. A total of 17 pNF tumor tissue specimens from the head and neck were collected at the Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine. Histologically, diagnosis of the Schwann cell region in pNF was achieved with hematoxylin-eosin staining, positive reactions for S100, SOX10, ERK and pERK , and low identification of Ki67 and SMA. Compared with normal nerve tissue, obviously increased nuclear YAP was detected in the Schwann cell region of pNF, with a mean nuclear staining rate of 67.11%. Based on the shNF1 Schwann cell model (the RSC96 cell line), with upregulated expression of RAS, ERK and pERK , p-YAP (Ser127) and p-YAP (Ser397) were significantly decreased and total YAP and nuclear YAP were increased. According to a confocal assay, the interference of shNF1 substantially promoted YAP nuclear translocation. Compared with control Schwann cells, the YAP inhibitor CA3 might have a more sensitive effect (IC50: NC=0.96±0.04, shNF1=0.71±0.02, P<0.05) on the shNF1 Schwann cell model than the classic MEK1/2 inhibitor selumetinib (IC50: NC=14.36±0.95, shNF1=24.83±0.98, P>0.05). For in vivo inhibition, the CA3 group and the selumetinib group displayed a similar inhibition effect with no significant difference. Increased nuclear translation and the functional state of YAP implies that the YAP-Hippo pathway might play an important role in the formation and remyelination of pNF. Compared with selumetinib, the YAP inhibitor can exhibit a similar but more sensitive effect on NF1-/-Schwann cells. These observations imply that YAP as a novel or adjuvant therapy target in the treatment of pNF.

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Section: Discussionmentioning

confidence: 99%

Increased nuclear translation of YAP might act as a potential therapeutic target for NF1-related plexiform neurofibroma

Liu¹,

You²,

Tian³

et al. 2021

Int. J. Med. Sci.

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“…Normally, activation of PI3K activates downstream protein kinases, PDK1, both PDK1 and Akt have a PH domain showing selectivity for phosphoinositides phosphorylated in position three produced by PI3K at the plasma membrane 33,34. PDK1-mediated phosphorylation is a key event in Akt activation 35,36. Subsequently, p-Akt could regulate the expression of many molecules to affect cell proliferation and apoptosis 37.…”

Section: Discussionmentioning

confidence: 99%

<p>Apiosporamide, A 4-hydroxy-2-pyridone Alkaloid, Induces Apoptosis Via PI3K/Akt Signaling Pathway In Osteosarcoma Cells</p>

Zhang¹,

Zhang²,

Bao³

et al. 2019

OTT

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BackgroundOsteosarcoma (OS) is a common primary malignant bone tumour in children and young adults. Apiosporamide, a 4-hydroxy-2-pyridone alkaloid from a deep-sea-derived fungus, Arthrinium sp. UJNMF0008, showed anti-proliferative effects toward a panel of human cancer cell lines, and the molecular mechanism in MG63 cells was then investigated in the current work.MethodsCell viability was determined with MTT method. Cell proliferation was detected using colony-formation assay. Screening electron microscope was used for morphology observation. Cell cycle and apoptosis was analysed via flow cytometry. Real-time PCR was conducted to evaluate the mRNA expression related with cell apoptosis. The expression levels of proteins related to capase-mediated apoptotic pathway and PI3K/Akt signalling pathway were detected by Western blotting.ResultsApiosporamide significantly decreased cell viability in cancer cells, and also exhibited excellent anti-proliferative effect. Apiosporamide caused cell cycle arrests at G0/G1 phase in MG63 cells. Moreover, apiosporamide induced apoptosis, activated caspase-3, caspase-8 and caspase-9, and regulated expression of Bax and Bcl-2 in MG63 cells. In addition, apiosporamide also attenuated PI3K/Akt signaling pathway.ConclusionApiosporamide effectively suppressed MG63 cells proliferation by inducing apoptosis through PI3K/Akt and caspase-associated apoptotic pathway.

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“…A member of the pyruvate dehydrogenase kinase (PDK) family, PDKs function to regulate carbohydrate metabolism in mammals by catalyzing oxidative decarboxylation of pyruvate [40]. Overexpression of PDKs is linked to tumor formation from antioxidants that increase cancer cell metabolism and survival [40,41]. From this, we suspect the observed PDK inhibition (Figure 9b) to possibly explain the decrease in superoxide radical production ( Figure 5a) as a result of controlled oxidative phosphorylation and glucose metabolism [40,42,43].…”

Section: Downregulated Processes Also Prevent Tumor Growth and Spreadmentioning

confidence: 98%

An Assessment of InP/ZnS as Potential Anti-Cancer Therapy: Quantum Dot Treatment Increases Apoptosis in HeLa Cells

Davenport

Horstmann

Patel

et al. 2021

JNT

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InP/ZnS quantum dots (QDs) are an emerging option in QD technologies for uses of fluorescent imaging as well as targeted drug and anticancer therapies based on their customizable properties. In this study we explored effects of InP/ZnS when treated with HeLa cervical cancer cells. We employed XTT viability assays, reactive oxygen species (ROS) analysis, and apoptosis analysis to better understand cytotoxicity extents at different concentrations of InP/ZnS. In addition, we compared the transcriptome profile from the QD-treated HeLa cells with that of untreated HeLa cells to identify changes to the transcriptome in response to the QD. RT-qPCR assay was performed to confirm the findings of transcriptome analysis, and the QD mode of action was illustrated. Our study determined both IC50 concentration of 69 µg/mL and MIC concentration of 167 µg/mL of InP/ZnS. It was observed via XTT assay that cell viability was decreased significantly at the MIC. Production of superoxide, measured by ROS assay with flow cytometry, was decreased, whereas levels of nitrogen radicals increased. Using analysis of apoptosis, we found that induced cell death in the QD-treated samples was shown to be significantly increased when compared to untreated cells. We conclude InP/ZnS QD to decrease cell viability by inducing stress via ROS levels, apoptosis induction, and alteration of transcriptome.

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PDK-1 mediated Hippo–YAP–IRS2 signaling pathway and involved in the apoptosis of non-small cell lung cancer cells

Cited by 16 publications

References 39 publications

Increased nuclear translation of YAP might act as a potential therapeutic target for NF1-related plexiform neurofibroma

Increased nuclear translation of YAP might act as a potential therapeutic target for NF1-related plexiform neurofibroma

<p>Apiosporamide, A 4-hydroxy-2-pyridone Alkaloid, Induces Apoptosis Via PI3K/Akt Signaling Pathway In Osteosarcoma Cells</p>

An Assessment of InP/ZnS as Potential Anti-Cancer Therapy: Quantum Dot Treatment Increases Apoptosis in HeLa Cells

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