Notch pathway inhibition mediated by arsenic trioxide depletes tumor initiating cells in small cell lung cancer

2022 ◽  
Author(s):  
Meng-Hang Yang ◽  
Bing Li ◽  
Ke-Jie Chang
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Arsenic Trioxide ◽  
Cell Lung Cancer ◽  
Notch Pathway ◽  
Small Cell ◽  
Small Cell Lung ◽  
Tumor Initiating Cells ◽  
Pathway Inhibition

scholarly journals 4198 Investigating the Role of Rab27B in Non-Small Cell Lung Cancer Tumor Initiating Cells

2020 ◽  
Vol 4 (s1) ◽  
pp. 98-98
Author(s):  
Danielle Beetler ◽  
Kayleah Beltran ◽  
Kayla Lewis ◽  
Verline Justilien
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cancer Cells ◽  
Cell Lung Cancer ◽  
Immunoblot Analysis ◽  
Small Cell ◽  
Small Gtpase ◽  
Small Cell Lung ◽  
Tumor Initiating Cells

OBJECTIVES/GOALS: Rab27B, a small GTPase, functions in exosome formation and secretion. Rab27B is overexpressed in non-small cell lung cancer (NSCLC) and predicts patient survival; however, little is known about its importance in NSCLC cells. Here, we investigated the role of Rab27B in NSCLC tumor initiating cells. METHODS/STUDY POPULATION: Tumor initiating cells (TICs) were enriched in a panel of NSCLC cell lines using low adherence spheroid cultures. QPCR and immunoblot analysis were used to compare Rab27B mRNA and protein expression, respectively, in adherent bulk cancer cells and TIC cultures. Lentiviral-packaged short hairpin RNAs (shRNAs) were used to knockdown Rab27B in PC9 and H1299 NSCLC TICs. The effects of Rab27B knockdown on PC9 and H1299 TIC expansion, transformed growth, and invasion were analyzed by MTT cell proliferation, soft agar colony formation, and Boyden chamber assays respectively. RESULTS/ANTICIPATED RESULTS: Quantitative PCR and immunoblot analysis showed that Rab27B expression is elevated in NSCLC TICs when compared to adherent bulk cancer cells. Efficient knockdown of Rab27B was achieved in PC9 and H1299 NSCLC TICs using two independent shRNA constructs. Rab27B knockdown cells exhibited decreased expansion as spheroid cultures, transformed growth, and invasion when compared to non-target shRNA control cells. Future experiments will focus on determining the importance of Rab27B in TIC exosome production and in vivo tumor growth and metastasis. DISCUSSION/SIGNIFICANCE OF IMPACT: Our results show that Rab27B is important in NSCLC TIC growth and invasion. Further studies are needed to determine the mechanism of Rab27B action. TICs have been linked to enhanced tumorigenic properties, suggesting that Rab27B could be a good candidate for therapeutic targeting of NSCLC TICs.

Abstract 372: Optimizing vertical MAPK pathway inhibition for RAS mutant non-small cell lung cancer

2017 ◽  
Author(s):  
Jens Köhler ◽  
Cloud P. Paweletz ◽  
Yanan Kuang ◽  
Prafulla Gokhale ◽  
Margaret K. Wilkens ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Mapk Pathway ◽  
Small Cell ◽  
Small Cell Lung ◽  
Pathway Inhibition

scholarly journals Glycine Decarboxylase Activity Drives Non-Small Cell Lung Cancer Tumor-Initiating Cells and Tumorigenesis

Cell ◽  
2012 ◽  
Vol 148 (5) ◽  
pp. 1066 ◽  
Author(s):  
Wen Cai Zhang ◽  
Ng Shyh-Chang ◽  
He Yang ◽  
Amit Rai ◽  
Shivshankar Umashankar ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Decarboxylase Activity ◽  
Glycine Decarboxylase ◽  
Small Cell Lung ◽  
Tumor Initiating Cells ◽  
Cancer Tumor

Long non-coding RNA and Notch regulation in non-small cell lung cancer

2020 ◽  
Vol 10 (1) ◽  
pp. 108-122
Author(s):  
Joanna Pancewicz
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Signaling Pathways ◽  
Cancer Progression ◽  
Cell Lung Cancer ◽  
Notch Pathway ◽  
Current Data ◽  
Small Cell ◽  
Small Cell Lung ◽  
Cancer Pathogenesis

Non-small cell lung cancer is one of the most commonly diagnosed cancer with a very high mortality rate. Trying to understand the mechanisms underlying the progression of this type of cancer, it is necessary to evaluate the changes occurring at molecular level in cancer cells. Besides the widely studied signaling pathways and genes which are dysregulated in NSCLC, there is a large group of non-coding RNAs involved in cancer pathogenesis. Those RNAs are tissue specific heterogeneous class of RNAs that play many functions in physiological condition in cells, nevertheless current data has shown that lncRNAs are also functional in different types of cancer. Moreover, it has been suggest that lncRNAs are involved in cancer progression by controlling key signaling pathways involved in diverse types of tumors. Notch signaling is one of those pathways, very often deregulated in NSCLC. Therefore in this review I summarized recent outcomes according the importance of lncRNAs in regulation of Notch pathway in the pathogenesis of NSCLC.

scholarly journals The SOX9-Aldehyde Dehydrogenase Axis Determines Resistance to Chemotherapy in Non-Small-Cell Lung Cancer

2019 ◽  
Vol 40 (2) ◽  
Author(s):  
Maria A. Voronkova ◽  
Liying W. Rojanasakul ◽  
Chayanin Kiratipaiboon ◽  
Yon Rojanasakul
Keyword(s):  
Lung Cancer ◽  
Transcription Factor ◽  
Small Cell Lung Cancer ◽  
Aldehyde Dehydrogenase ◽  
Cell Lung Cancer ◽  
Drug Targets ◽  
Small Cell ◽  
Luciferase Reporter ◽  
Small Cell Lung ◽  
Tumor Initiating Cells

ABSTRACT Chemotherapy resistance and tumor relapse are the major contributors to low patient survival, and both have been largely attributed to cancer stem-like cells (CSCs) or tumor-initiating cells (TICs). Moreover, most conventional therapies are not effective against CSCs, which necessitates the discovery of CSC-specific biomarkers and drug targets. Here, we demonstrated that the embryonic transcription factor SOX9 is an important regulator of acquired chemoresistance in non-small-cell lung cancer (NSCLC). Our results show that SOX9 expression is elevated in NSCLC cells after treatment with the chemotherapeutic cisplatin and that overexpression of SOX9 correlates with worse overall survival in lung cancer patients. We further demonstrated that SOX9 knockdown increases cellular sensitivity to cisplatin, whereas its overexpression promotes drug resistance. Moreover, this transcription factor promotes the stem-like properties of NSCLC cells and increases their aldehyde dehydrogenase (ALDH) activity, which was identified to be the key mechanism of SOX9-induced chemoresistance. Finally, we showed that ALDH1A1 is a direct transcriptional target of SOX9, based on chromatin immunoprecipitation and luciferase reporter assays. Taken together, our novel findings on the role of the SOX9-ALDH axis support the use of this CSC regulator as a prognostic marker of cancer chemoresistance and as a potential drug target for CSC therapy.

scholarly journals Arsenic Trioxide Suppresses Tumor Growth through Antiangiogenesis via Notch Signaling Blockade in Small-Cell Lung Cancer

2019 ◽  
Vol 2019 ◽  
pp. 1-9
Author(s):  
Meng-Hang Yang ◽  
Ke-Jie Chang ◽  
Bing Li ◽  
Wan-Sheng Chen
Keyword(s):  
Lung Cancer ◽  
Tumor Growth ◽  
Small Cell Lung Cancer ◽  
Notch Signaling ◽  
Arsenic Trioxide ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Morphological Development ◽  
Small Cell Lung ◽  
Chemotherapy Drugs

Small-cell lung cancer (SCLC) is a highly malignant type of lung cancer with no effective second-line chemotherapy drugs. Arsenic trioxide (As2O3) was reported to exert antiangiogenesis activities against lung cancer and induce poor development of vessel structures, similar to the effect observed following the blockade of Notch signaling. However, there are no direct evidences on the inhibitory effects of As2O3 on tumor growth and angiogenesis via blockade of Notch signaling in SCLC. Here, we found that As2O3 significantly inhibited the tumor growth and angiogenesis in SCLC and reduced the microvessel density. As2O3 disturbed the morphological development of tumor vessels and downregulated the protein levels of delta-like canonical Notch ligand 4 (Dll4), Notch1, and Hes1 in vivo. DAPT, a Notch signaling inhibitor, exerted similar effects in SCLC. We found that both As2O3 treatment and Notch1 expression knockdown resulted in the interruption of tube formation by human umbilical vein endothelial cells (HUVECs) on Matrigel. As2O3 had no effects on Dll4 level in HUVECs but significantly inhibited the expression of Notch1 and its downstream gene Hes1 regardless of Dll4 overexpression or Notch1 knockdown. These findings suggest that the antitumor activity of As2O3 in SCLC was mediated via its antiangiogenic effect through the blockade of Notch signaling, probably owing to Notch1 targeting.

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