Valproic acid (VPA) enhances cisplatin sensitivity of non-small cell lung cancer cells via HDAC2 mediated down regulation of ABCA1

Abstract Valproic acid (VPA) has been suggested to be a histone deacetylase inhibitor (HDACI). Our present study revealed that VPA at 1 mm, which had no effect on cell proliferation, can significantly increase the sensitivity of non-small cell lung cancer (NSCLC) cells to cisplatin (DDP). VPA treatment markedly decreased the mRNA and protein levels of ABCA1, while had no significant effect on ABCA3, ABCA7 or ABCB10. Luciferase reporter assays showed that VPA can decrease the ABCA1 promoter activity in both A549 and H358 cells. VPA treatment also decreased the phosphorylation of SP1, which can bind to −100 and −166 bp in the promoter of ABCA1. While the phosphorylation of c-Fos and c-Jun were not changed in VPA treated NSCLC cells. Over expression of HDAC2 attenuated VPA induced down regulation of ABCA1 mRNA expression and promoter activities. Over expression of HDAC2 also attenuated VPA induced DDP sensitivity of NSCLC cells. These data revealed that VPA can increase the DDP sensitivity of NSCLC cells via down regulation of ABCA1 through HDAC2/SP1 signals. It suggested that combination of VPA and anticancer drugs such as DDP might be great helpful for treatment of NSCLC patients.

Download Full-text

Faculty Opinions recommendation of Down-regulation of miR-214 inhibits proliferation and glycolysis in non-small-cell lung cancer cells via down-regulating the expression of hexokinase 2 and pyruvate kinase isozyme M2.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.733460129.793580846 ◽

2020 ◽

Author(s):

Leonardo Salmena

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cancer Cells ◽

Pyruvate Kinase ◽

Cell Lung Cancer ◽

Small Cell ◽

Lung Cancer Cells ◽

Small Cell Lung ◽

Down Regulation ◽

Hexokinase 2

Download Full-text

Midazolam increases cisplatin-sensitivity in non-small cell lung cancer (NSCLC) via the miR-194-5p/HOOK3 axis

Cancer Cell International ◽

10.1186/s12935-021-02104-6 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Tingting Sun ◽

Jing Chen ◽

Xuechao Sun ◽

Guonian Wang

Keyword(s):

Lung Cancer ◽

Cell Proliferation ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Cell Apoptosis ◽

Cisplatin Resistance ◽

Small Cell ◽

Luciferase Reporter ◽

Small Cell Lung ◽

Cisplatin Sensitivity

Abstract Backgrounds As previously reported, midazolam anesthesia exerts tumor-suppressing effects in non-small cell lung cancer (NSCLC), but the regulating effects of this drug on cisplatin-resistance in NSCLC have not been studied. Thus, we designed this study to investigate this issue and preliminarily delineate the potential molecular mechanisms. Methods We performed MTT assay and trypan blue staining assay to measure cell proliferation and viability. Cell apoptosis was examined by FCM. qRT-PCR and immunoblotting were performed to determine the expression levels of genes. The targeting sites between genes were predicted by bioinformatics analysis and were validated by dual-luciferase reporter gene system assay. Mice tumor-bearing models were established and the tumorigenesis was evaluated by measuring tumor weight and volume. Immunohistochemistry (IHC) was used to examine the pro-proliferative Ki67 protein expressions in mice tumor tissues. Results The cisplatin-resistant NSCLC (CR-NSCLC) cells were treated with high-dose cisplatin (50 μg/ml) and low-dose midazolam (10 μg/ml), and the results showed that midazolam suppressed cell proliferation and viability, and promoted cell apoptosis in cisplatin-treated CR-NSCLC cells. In addition, midazolam enhanced cisplatin-sensitivity in CR-NSCLC cell via modulating the miR-194-5p/hook microtubule-tethering protein 3 (HOOK3) axis. Specifically, midazolam upregulated miR-194-5p, but downregulated HOOK3 in the CR-NSCLC cells, and further results validated that miR-194-5p bound to the 3’ untranslated region (3’UTR) of HOOK3 mRNA for its inhibition. Also, midazolam downregulated HOOK3 in CR-NSCLC cells by upregulating miR-194-5p. Functional experiments validated that both miR-194-5p downregulation and HOOK3 upregulation abrogated the promoting effects of midazolam on cisplatin-sensitivity in CR-NSCLC cells. Conclusions Taken together, this study found that midazolam anesthesia reduced cisplatin-resistance in CR-NSCLC cells by regulating the miR-194-5p/HOOK3 axis, implying that midazolam could be used as adjuvant drug for NSCLC treatment in clinical practices.

Download Full-text

Diethylstilbestrol, a Novel ANO1 Inhibitor, Exerts an Anticancer Effect on Non-Small Cell Lung Cancer via Inhibition of ANO1

International Journal of Molecular Sciences ◽

10.3390/ijms22137100 ◽

2021 ◽

Vol 22 (13) ◽

pp. 7100

Author(s):

Yohan Seo ◽

Sung Baek Jeong ◽

Joo Han Woo ◽

Oh-Bin Kwon ◽

Sion Lee ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

High Throughput Screening ◽

Fluorescent Protein ◽

Yellow Fluorescent Protein ◽

Small Cell ◽

Channel Activity ◽

Small Cell Lung ◽

Protein Levels

Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related mortality; thus, therapeutic targets continue to be developed. Anoctamin1 (ANO1), a novel drug target considered for the treatment of NSCLC, is a Ca2+-activated chloride channel (CaCC) overexpressed in various carcinomas. It plays an important role in the development of cancer; however, the role of ANO1 in NSCLC is unclear. In this study, diethylstilbestrol (DES) was identified as a selective ANO1 inhibitor using high-throughput screening. We found that DES inhibited yellow fluorescent protein (YFP) fluorescence reduction caused by ANO1 activation but did not inhibit cystic fibrosis transmembrane conductance regulator channel activity or P2Y activation-related cytosolic Ca2+ levels. Additionally, electrophysiological analyses showed that DES significantly reduced ANO1 channel activity, but it more potently reduced ANO1 protein levels. DES also inhibited the viability and migration of PC9 cells via the reduction in ANO1, phospho-ERK1/2, and phospho-EGFR levels. Moreover, DES induced apoptosis by increasing caspase-3 activity and PARP-1 cleavage in PC9 cells, but it did not affect the viability of hepatocytes. These results suggest that ANO1 is a crucial target in the treatment of NSCLC, and DES may be developed as a potential anti-NSCLC therapeutic agent.

Download Full-text

Elevating CDCA3 levels in non-small cell lung cancer enhances sensitivity to platinum-based chemotherapy

Communications Biology ◽

10.1038/s42003-021-02136-8 ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Katrina Kildey ◽

Neha S. Gandhi ◽

Katherine B. Sahin ◽

Esha T. Shah ◽

Eric Boittier ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Genome Instability ◽

Small Cell ◽

Small Cell Lung ◽

Protein Levels ◽

Platinum Based Chemotherapy ◽

Platinum Agents

AbstractPlatinum-based chemotherapy remains the cornerstone of treatment for most non-small cell lung cancer (NSCLC) cases either as maintenance therapy or in combination with immunotherapy. However, resistance remains a primary issue. Our findings point to the possibility of exploiting levels of cell division cycle associated protein-3 (CDCA3) to improve response of NSCLC tumours to therapy. We demonstrate that in patients and in vitro analyses, CDCA3 levels correlate with measures of genome instability and platinum sensitivity, whereby CDCA3high tumours are sensitive to cisplatin and carboplatin. In NSCLC, CDCA3 protein levels are regulated by the ubiquitin ligase APC/C and cofactor Cdh1. Here, we identified that the degradation of CDCA3 is modulated by activity of casein kinase 2 (CK2) which promotes an interaction between CDCA3 and Cdh1. Supporting this, pharmacological inhibition of CK2 with CX-4945 disrupts CDCA3 degradation, elevating CDCA3 levels and increasing sensitivity to platinum agents. We propose that combining CK2 inhibitors with platinum-based chemotherapy could enhance platinum efficacy in CDCA3low NSCLC tumours and benefit patients.

Download Full-text

Down‐regulation of RCC1 sensitizes immunotherapy by up‐regulating PD‐L1 via p27 kip1 /CDK4 axis in non‐small cell lung cancer

Journal of Cellular and Molecular Medicine ◽

10.1111/jcmm.16383 ◽

2021 ◽

Author(s):

Xiaozhu Zeng ◽

Maoxi Zhong ◽

Yumeng Yang ◽

Zhi Wang ◽

Yuxi Zhu

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Small Cell ◽

Small Cell Lung ◽

Down Regulation ◽

P27 Kip1

Download Full-text

LncRNA MCM3AP-AS1 sponges miR-148a to enhance cell invasion and migration in small cell lung cancer

BMC Cancer ◽

10.1186/s12885-021-08365-8 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Hua Luo ◽

Yukun Zhang ◽

Guangmei Qin ◽

Bing Jiang ◽

Lili Miao

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Cell Invasion ◽

Small Cell ◽

Small Cell Lung ◽

Invasion And Migration ◽

Protein Levels ◽

Underlying Mechanisms ◽

And Migration

Abstract Background MCM3AP-AS1 is a recently characterized lncRNA playing an oncogenic role in several cancers. However, its role in lung cancer remains unknown. Here, we aimed to explore the functions of MCM3AP-AS1 in small cell lung cancer (SCLC) and the possible underlying mechanisms. Methods MCM3AP-AS1 and ROCK1 levels in SCLC patients were analyzed by qPCR. RNA pull-down and luciferase assays were performed to analyze the interaction between MCM3AP-AS1 and miR-148a. ROCK1 mRNA and protein levels were detected by qPCR and Western blot, respectively. Cell invasion and migration were analyzed by Transwell assays. Results MCM3AP-AS1 was upregulated in patients with SCLC, and a high MCM3AP-AS1 level was accompanied by a low survival rate. The binding of MCM3AP-AS1 to miR-148a predicted by bioinformatics analysis was verified by RNA pull-down and luciferase assays. However, MCM3AP-AS1 and miR-148a did not affect each other’s expression. ROCK1 was upregulated in SCLC tissues and positively correlated with MCM3AP-AS1. In SCLC cells, MCM3AP-AS1 overexpression increased ROCK1 and promoted cancer cell invasion and migration, while miR-148a overexpression showed the opposite effects and attenuated the effects of MCM3AP-AS1 overexpression on ROCK1 expression and cell behaviors. Conclusions MCM3AP-AS1 sponges miR-148a, thereby increasing SCLC cell invasion and migration via upregulating ROCK1 expression.

Download Full-text

MicroRNA-138 Inhibits Cell Growth, Invasion, and EMT of Non-Small Cell Lung Cancer via SOX4/p53 Feedback Loop

Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics ◽

10.3727/096504017x14973124850905 ◽

2018 ◽

Vol 26 (3) ◽

pp. 385-400 ◽

Cited By ~ 14

Author(s):

Dandan Li ◽

Changjun He ◽

Junfeng Wang ◽

Yanbo Wang ◽

Jianlong Bu ◽

...

Keyword(s):

Lung Cancer ◽

Cell Growth ◽

Small Cell Lung Cancer ◽

Cell Lines ◽

Cell Lung Cancer ◽

Feedback Loop ◽

Molecular Mechanisms ◽

Small Cell ◽

Luciferase Reporter ◽

Small Cell Lung

Many studies have shown that downregulation of miR-138 occurs in a variety of cancers including non-small cell lung cancer (NSCLC). However, the precise mechanisms of miR-138 in NSCLC have not been well clarified. In this study, we investigated the biological functions and molecular mechanisms of miR-138 in NSCLC cell lines, discussing whether it could turn out to be a therapeutic biomarker of NSCLC in the future. In our study, we found that miR-138 is downregulated in NSCLC tissues and cell lines. Moreover, the low level of miR-138 was associated with increased expression of SOX4 in NSCLC tissues and cell lines. Upregulation of miR-138 significantly inhibited proliferation of NSCLC cells. In addition, invasion and EMT of NSCLC cells were suppressed by overexpression of miR-138. However, downregulation of miR-138 promoted cell growth and metastasis of NSCLC cells. Bioinformatics analysis predicted that SOX4 was a potential target gene of miR-138. Next, luciferase reporter assay confirmed that miR-138 could directly target SOX4. Consistent with the effect of miR-138, downregulation of SOX4 by siRNA inhibited proliferation, invasion, and EMT of NSCLC cells. Overexpression of SOX4 in NSCLC cells partially reversed the effect of miR-138 mimic. In addition, decreased SOX4 expression could increase the level of miR-138 via upregulation of p53. Introduction of miR-138 dramatically inhibited growth, invasion, and EMT of NSCLC cells through a SOX4/p53 feedback loop.

Download Full-text