Upregulation of endogenous TRAIL-elicited apoptosis is essential for metformin-mediated antitumor activity against TNBC and NSCLC

Liu, Shuang; Polsdofer, Erik; Zhou, Lukun; Ruan, Sanbao; Lyu, Hui; Hou, Defu; Líu, Hao; Thor, Ann D.; He, Zhiwei

doi:10.1016/j.omto.2021.04.012

Cited by 12 publications

(9 citation statements)

References 60 publications

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“…Previous studies suggest that β3GlcNAcT family members are closely related to the occurrence and development of malignant tumors ( 23 - 25 ). B3GNT3 was found to be closely related to the occurrence and development of breast cancer ( 26 ), but there was no report on its relationship with lung adenocarcinoma. In this study, various information of lung adenocarcinoma patients was obtained from the TCGA database at first, and then the patients were divided into groups with high B3GNT3 expression and low B3GNT3 expression.…”

Section: Discussionmentioning

confidence: 99%

Experimental study on the suppressive effect of B3GNT3 on the apoptosis of lung adenocarcinoma cells and its application in early screening for lung adenocarcinoma

Shuai¹,

Peng²,

Lv³

et al. 2023

J Thorac Dis

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Background: Lung adenocarcinoma, as a common histological type in lung cancer, the overall survival is very low, and the prognosis is poor because it is difficult to find and easily recurs. Therefore, this study aimed to explore the role of the secreted protein beta-1,3-N-acetylglucosaminyltransferase 3 (B3GNT3) in the development of lung adenocarcinoma and to evaluate its potential significance for early clinical biomarker screening. Methods:The mRNA expression profiles of patients with lung adenocarcinoma and normal controls were analyzed via The Cancer Genome Atlas (TCGA) database. Serum samples of clinical lung cancer patients and healthy people were obtained, and the differences in B3GNT3 expression in different stages of lung adenocarcinoma and in healthy tissues were compared. Kaplan-Meier (K-M) curves were drawn to clarify the influence of high and low expression of B3GNT3 on the prognosis of patients. Peripheral blood samples from patients with lung adenocarcinoma and healthy people were obtained clinically, and receiver operating characteristic (ROC) curves were drawn to clarify the sensitivity and specificity of B3GNT3 expression for the diagnosis of lung adenocarcinoma. Lung adenocarcinoma cells were cultured in vitro, the expression of B3GNT3 was knocked down by lentivirus infection. The expression of the apoptosis-associated genes was detected by reverse transcription-polymerase chain reaction (RT-PCR). Results:The secreted protein B3GNT3 is significantly differentially expressed in the serum of patients with lung adenocarcinoma versus normal controls. Subgroup analysis according to lung adenocarcinoma clinical stage showed that the higher the clinical stage of lung adenocarcinoma was, the higher the B3GNT3 expression. Enzyme-linked immunosorbent assay (ELISA) revealed that B3GNT3 expression was significantly increased in the serum of patients with lung adenocarcinoma and significantly decreased after surgery. By inhibiting programmed cell death-ligand 1 (PD-L1), the level of apoptosis was significantly increased and the proliferative capacity was significantly inhibited. In contrast, the level of apoptosis was significantly increased and the proliferation ability was significantly inhibited after simultaneous overexpression of B3GNT3 and inhibition of PD-L1.Conclusions: High expression of the secreted protein B3GNT3 in lung adenocarcinoma is closely related to prognosis and can serve as a potential biological marker for the early screening of lung adenocarcinoma.

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Section: Discussionmentioning

confidence: 99%

Experimental study on the suppressive effect of B3GNT3 on the apoptosis of lung adenocarcinoma cells and its application in early screening for lung adenocarcinoma

Shuai¹,

Peng²,

Lv³

et al. 2023

J Thorac Dis

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“…Cell growth/viability was measured by MTS assays with CellTiter 96 Aqueous One Solution kit (Promega, Madison, WI) as described previously [ 47 – 49 ]. Cells were seeded in 96-well plates and treated with the relevant agents.…”

Section: Methodsmentioning

confidence: 99%

“…Cells were seeded in a 24-well plate overnight. After treatment, cells were stained with the LIVE/DEAD Cell Imaging kit (488/570) (Thermo Fisher Scientific, Inc., Waltham, MA) as described previously [ 49 ]. After incubation at room temperature in the dark, the cells were observed under EVOS FLoid Cell Imaging System (Thermo Fisher Scientific) and measured for live cells (green) with Green-Light Channel and dead cells (red) with Red-Light Channel.…”

Section: Methodsmentioning

confidence: 99%

HER3 functions as an effective therapeutic target in triple negative breast cancer to potentiate the antitumor activity of gefitinib and paclitaxel

Lyu,

Shen,

Ruan

et al. 2023

Cancer Cell Int

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Background Triple negative breast cancer (TNBC) represents a significant clinical challenge. Chemotherapy remains the mainstay for a large part of TNBC patients, whereas drug resistance and tumor recurrence frequently occur. It is in urgent need to identify novel molecular targets for TNBC and develop effective therapy against the aggressive disease. Methods Immunohistochemistry was performed to examine the expression of HER3 in TNBC samples. Western blots were used to assess protein expression and activation. Cell proliferation and viability were determined by cell growth (MTS) assays. TCGA databases were analyzed to correlate HER3 mRNA expression with the clinical outcomes of TNBC patients. Specific shRNA was used to knockdown HER3 expression. IncuCyte system was utilized to monitor cell growth and migration. LIVE/DEAD Cell Imaging was to detect live and dead cells. HER3 recognition by our anti-HER3 monoclonal antibody (mAb) 4A7 was verified by ELISA, flow cytometry, and co-immunoprecipitation assays. Orthotopic tumor models were established in nude mice to determine the capability of TNBC cells forming tumors and to test if our mAb 4A7 could potentiate the antitumor activity of paclitaxel in vivo. Results Elevated expression of HER3 was observed in approximately half of the TNBC specimens and cell lines tested. Analyses of TCGA databases found that the TNBC patients with high HER3 mRNA expression in the tumors showed significantly worse overall survival (OS) and relapse-free survival (RFS) than those with low HER3 expression. Specific knockdown of HER3 markedly inhibited TNBC cell proliferation and mammosphere formation in vitro and tumor growth in vivo. Our mAb 4A7 abrogated heregulin (a ligand for HER3), but not SDF-1 (a ligand for CXCR4)-induced enhancement of TNBC cell migration. Combinations of 4A7 and the EGFR-tyrosine kinase inhibitor (TKI) gefitinib dramatically decreased the levels of phosphorylated HER3, EGFR, Akt, and ERK1/2 in TNBC cells and potently induced growth inhibition and cell death. Moreover, 4A7 in combination with paclitaxel exerted significant antitumor activity against TNBC in vitro and in vivo. Conclusions Our data demonstrate that increased HER3 is an effective therapeutic target for TNBC and our anti-HER3 mAb (4A7) may enhance the efficacy of gefitinib or paclitaxel in TNBC.

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“…Pokazano je u više istraživanja da sam metformin pokazuje citotoksični efekat prema ćelijama NSCLC in vitro, pri čemu se kao mehanizam ćelijske smrti opisuje apoptoza i to pokretanje spoljašnjeg puta praćeno aktivacijom kaspaze 8 (30). Takođe, opisuje se i pokretanje apoptoze koje je posledica smanjenja antiapoptotskog Bcl-2 i povećanja proapoptoskog Bax proteina, što aktivira mitohondrijalni, unutrašnji put pokretanja apoptoze (31).…”

Section: Metformin and The Possible Mechanisms Of Cytotoxic Effects S...unclassified

“…It has been shown in several studies that metformin has a cytotoxic effect on NSCLC cells in vitro, while apoptosis has been described as the mechanism of cell death, namely the triggering of extrinsic pathway accompanied by the activation of caspase 8 (30). The activation of apoptosis as the consequence of decrease in antiapoptotic Bcl-2 and increase in proapoptotic Bax protein which activates the mitochondrial, intrinsic pathway of apoptosis activation (31), has also been described.…”

Section: Metformin and The Possible Mechanisms Of Cytotoxic Effects S...mentioning

confidence: 99%

The role of metformin in the treatment of non-small cell lung cancer

Ljubičić¹,

Pešić²,

Pavlović³

et al. 2022

Zdravstvena zaštita

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Out of the all newly diagnosed lung cancers, non-small cell lung carcinoma (NSCLC) comprises 80-85%. When treating advanced stages of the disease, conventional therapy shows poor results, which implies that there is a need for new drugs that will improve the response to current therapy. Metformin, drug used to threat Diabetes mellitus showed promising results in preclinical and retrospective clinical studies. We have analyzed prospective clinical trials investigating the combined effect of conventional therapy and metformin in treating lung cancer, as well as preclinical studies investigating its possible mechanisms of action published in PubMed database in the last 10 years. Several studies indicated that combination therapy with metformin led to the improvement in categories like overal survival (OS) and progression-free survival (PFS). However, the number of studies is limited and is characterized by a low number of subjects, as well as by a reduced compliance in subjects using metformin. Preclinical studies suggest cytotoxic effects of metformin, activation of apoptosis, as well as synergistic effect with chemotherapeutics, radiotherapy and biological agents used. The relevance of determined results is questionable, taking into account high metformin concentrations used in vitro. Based on the clinical studies published in the last ten years, there is insufficient data to conclude whether metformin improves prognostic factors in comparison to the conventional therapy. It is also not clear which mechanisms are responsible for possible beneficial effects of metformin. Future preclinical studies thus have to be better designed in order to increase their translational potential, while clinical studies have to be better controlled with improved selection and higher number of subjects enrolled.

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Upregulation of endogenous TRAIL-elicited apoptosis is essential for metformin-mediated antitumor activity against TNBC and NSCLC

Cited by 12 publications

References 60 publications

Experimental study on the suppressive effect of B3GNT3 on the apoptosis of lung adenocarcinoma cells and its application in early screening for lung adenocarcinoma

Experimental study on the suppressive effect of B3GNT3 on the apoptosis of lung adenocarcinoma cells and its application in early screening for lung adenocarcinoma

HER3 functions as an effective therapeutic target in triple negative breast cancer to potentiate the antitumor activity of gefitinib and paclitaxel

The role of metformin in the treatment of non-small cell lung cancer

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