Activity and molecular targets of pioglitazone via blockade of proliferation, invasiveness and bioenergetics in human NSCLC

Ciaramella, Vincenza; Sasso, Ferdinando Carlo; Liello, Raimondo Di; Corte, Carminia Maria Della; Barra, Giusi; Viscardi, Giuseppe; Esposito, Giovanna; Sparano, Francesca; Troiani, Teresa; Martinelli, Erika; Orditura, Michele; Vita, Ferdinando De; Ciardiello, Fortunato; Morgillo, Floriana

doi:10.1186/s13046-019-1176-1

Cited by 35 publications

(29 citation statements)

References 29 publications

(31 reference statements)

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“…So GCNT2 may be a novel gene contributing to metastasis with preferential expression in lung cancer, implying that blocking the TGFβ/GCNT2 signal pathway is a promising approach for targeting metastatic NSCLC. Furthermore, we found that APEX1 can activate the TGFβ/SAMD3 signal pathway by promoting lung cancer cells proliferation, as described previously [50]. For the TGFβ/SMAD3 signaling pathway, receptor-activated SAMD complexes activate or repress their target gene promoters.…”

Section: Validation Of Apex1-regulated Gene Expression and Alternativsupporting

confidence: 86%

APEX1 regulates alternative splicing of key tumorigenesis genes in non-small-cell lung cancer

Peng

Chen

et al. 2020

Preprint

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Background: Aberrant alternative splicing (AS) contributes to tumor progression. Previous studies have shown that apurinic-apyrimidinic endonuclease-1 (APEX1) is involved in tumor progression. It is unknown whether APEX1 functions in tumor progression by regulation of AS. It is also unknown whether APEX1 can regulate non-small-cell lung cancer (NSCLC) proliferation and apoptosis. Methods: We analyzed APEX1 expression levels in 517 lung NSCLC samples from the TCGA (Cancer Genome Atlas) database. The impact of APEX1 over expression on A549 cell proliferation and apoptosis was detected by the methyl thiazolyl tetrazolium assay and by flow cytometry. The transcriptome of A549 cells with and without APEX1 over expression was determined by Illumina sequencing, followed by analysis of AS. RT-qPCR validated APEX1 in A549 cells. Results: We have successfully applied RNA-seq technology to demonstrate APEX1 regulation of AS. APEX1 expression was shown to be upregulated in NSCLC samples and to reduce cell proliferation and induce apoptosis of A549 cells. Further, APEX1 regulated AS of key tumorigenesis genes involved in cancer proliferation and apoptosis within the MAPK and Wnt signaling pathways. Each of these pathways are involved in lung cancer progression. Validated AS events regulated by APEX1 were located in key tumorigenesis genes; AXIN1 (axis inhibition protein 1), GCNT2 (N-acetyl glucosaminyl transferase 2), and SMAD3 (SMAD Family Member 3). These genes encode signaling pathway transcription regulatory factors. Conclusions: We found that increased expression of APEX1 in NSCLC is an independent prognostic factor related to tumor progression. Therefore, APEX1 regulation of AS may serve as a molecular marker or therapeutic target for NSCLC treatment.

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Section: Validation Of Apex1-regulated Gene Expression and Alternativsupporting

confidence: 86%

APEX1 regulates alternative splicing of key tumorigenesis genes in non-small-cell lung cancer

Peng

Chen

et al. 2020

Preprint

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“…TZD18, a dual PPARγ/α ligand, reduced the growth and increased the apoptosis of human gastric cancer cells by increasing the expression of BAX and p27kip1 and decreasing Bcl-2 (Ma et al, 2019). Similar activity was observed for renal carcinoma cells (Wu et al, 2019), cutaneous squamous cell carcinoma cells (Wolff et al, 2019), non-small cell lung carcinoma (Liu and Fang, 1983; Ciaramella et al, 2019) and prostate cancer cells (Masure et al, 1983). Ciaramella et al (2019) also correlated the anti-cancer activity of PPARγ to its effects on cancer microenvironment bioenergetics and metabolism.…”

Section: Potential Effect Of Pparγ Agonists On Cancersupporting

confidence: 59%

Pharmacological Treatment of Chemotherapy-Induced Neuropathic Pain: PPARγ Agonists as a Promising Tool

et al. 2019

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Chemotherapy-induced neuropathic pain (CINP) is one of the most severe side effects of anticancer agents, such as platinum-and taxanes-derived drugs (oxaliplatin, cisplatin, carboplatin and paclitaxel). CINP may even be a factor of interruption of treatment and consequently increasing the risk of death. Besides that, it is important to take into consideration that the incidence of cancer is increasing worldwide, including colorectal, gastric, lung, cervical, ovary and breast cancers, all treated with the aforementioned drugs, justifying the concern of the medical community about the patient's quality of life. Several physiopathological mechanisms have already been described for CINP, such as changes in axonal transport, mitochondrial damage, increased ion channel activity and inflammation in the central nervous system (CNS). Another less frequent event that may occur after chemotherapy, particularly under oxaliplatin treatment, is the central neurotoxicity leading to disorders such as mental confusion, catatonia, hyporeflexia, etc. To date, no pharmacological therapy has shown satisfactory effect in these cases. In this scenario, duloxetine is the only drug currently in clinical use. Peroxisome proliferator-activated receptors (PPARs) belong to the class of nuclear receptors and are present in several tissues, mainly participating in lipid and glucose metabolism and inflammatory response. There are three PPAR isoforms: α, β/δ and γ. PPARγ, the protagonist of this review, is expressed in adipose tissue, large intestine, spleen and neutrophils. This subtype also plays important role in energy balance, lipid biosynthesis and adipogenesis. The effects of PPARγ agonists, known for their positive activity on type II diabetes mellitus, have been explored and present promising effects in the control of neuropathic pain, including CINP, and also cancer. This review focuses largely on the mechanisms involved in chemotherapy-induced neuropathy and the effects of the activation of PPARγ to treat CINP. It is the aim of this review to help understanding and developing novel CINP therapeutic strategies integrating PPARγ signalling.

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“…During the progression of EMT, the expression of epithelial markers such as E-cadherin was usually downregulated, while the expression of mesenchymal markers such as N-cadherin and vimentin was upregulated [23]. Previous studies have reported that pioglitazone restrained the proliferation and invasion of NSCLC cells via downregulating TGF-β to weaken EMT, and DEHP activated EMT via Wnt/β-catenin signal transduction pathway to promote the progress of NSCLC [24,25]. Such studies indicates that EMT is a crucial mechanism for the progression of NSCLC.…”

Section: Discussionmentioning

confidence: 99%

NudCD1 Promotes the Proliferation and Metastasis of Non-Small Cell Lung Cancer Cells through the Activation of IGF1R-ERK1/2

Xia

Zhang³

2020

Pathobiology

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Background: NudC domain containing 1 (NudCD1) is an oncoprotein related to diverse cancers. This study aims to investigate the expression, role, and regulatory mechanism of NudCD1 in non-small cell lung cancer (NSCLC). Methods: qRT-PCR, Western blot, and immunohistochemistry were performed to detect the expressions of NudCD1 in NSCLC tissues and cell lines. The correlation between NudCD1 expression and clinical features was determined by the χ 2 test. Besides, shRNA was used to construct the NudCD1 low expression model of NCI-H1299 and NCI-H460 cells, and CCK-8 and transwell assay were conducted to monitor the changes of proliferation, migration, and invasion of cancer cells. The expression levels of epithelial-mesenchymal transition markers and IGF1R-ERK1/2 signaling pathway proteins were detected by Western blot. Results: The expression of NudCD1 in NSCLC was higher than that in normal tissues, and the increased expression of NudCD1 was significantly correlated with increased T stage and lymph node metastasis. Moreover, patients with high expression of NudCD1 had worse prognosis. NudCD1 knockdown was proven to impede the proliferation but facilitate the migration and invasion of cancer cells. Furthermore, knockdown of NudCD1 resulted in an increase in the expression of E-cadherin and a decrease in the expression of vimentin. We also observed that NudCD1 overexpression promoted the phosphorylation of IGF1R and ERK1/2 proteins. Conclusion: NudCD1 promotes the proliferation and metastasis of NSCLC cells via activation of IGF1R-ERK1/2, which indicates that NudCD1 may be a potential therapy target of NSCLC.

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Activity and molecular targets of pioglitazone via blockade of proliferation, invasiveness and bioenergetics in human NSCLC

Cited by 35 publications

References 29 publications

APEX1 regulates alternative splicing of key tumorigenesis genes in non-small-cell lung cancer

APEX1 regulates alternative splicing of key tumorigenesis genes in non-small-cell lung cancer

Pharmacological Treatment of Chemotherapy-Induced Neuropathic Pain: PPARγ Agonists as a Promising Tool

NudCD1 Promotes the Proliferation and Metastasis of Non-Small Cell Lung Cancer Cells through the Activation of IGF1R-ERK1/2

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