scholarly journals Survival Function of Protein Kinase Cι as a Novel Nitrosamine 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone-activated Bad Kinase

2005 ◽  
Vol 280 (16) ◽  
pp. 16045-16052 ◽  
Author(s):  
Zhaohui Jin ◽  
Meiguo Xin ◽  
Xingming Deng
Keyword(s):  
Lung Cancer ◽  
Protein Kinase ◽  
Cancer Cells ◽  
Adrenergic Receptor ◽  
Human Lung ◽  
Small Cell ◽  
Lung Cancer Cells ◽  
Human Lung Cancer ◽  
Small Cell Lung ◽  
Human Lung Cancer Cells

Nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is formed by nitrosation of nicotine and has been identified as the most potent carcinogen in cigarette smoke. NNK cannot only induce DNA damage but also promotes the survival of human lung cancer cells. Protein kinase C (PKC)ι is an atypical PKC isoform and plays an important role in cell survival, but the downstream survival substrate(s) is not yet identified. Bad, a proapoptotic BH3-only member of Bcl2 family, is co-expressed with PKCι in both small cell lung cancer and non-small cell lung cancer cells. We discovered that NNK potently induces multisite Bad phosphorylation at Ser-112, Ser-136, and Ser-155 via activation of PKCι in association with increased survival of human lung cancer cells. Purified, active PKCι can directly phosphorylate both endogenous and recombinant Bad at these three sites and disrupt Bad/Bcl-XL bindingin vitro. Overexpression of PKCι results in an enhancement of Bad phosphorylation. NNK also stimulates activation of c-Src, which is a known PKCι upstream kinase. Treatment of cells with the PKC inhibitor (staurosporine) or a Src-specific inhibitor (PP2) can block NNK-induced Bad phosphorylation and promote apoptotic cell death. The β-adrenergic receptor inhibitor propranolol blocks both NNK-induced activation of PKCι and Bad phosphorylation, indicating that NNK-induced Bad phosphorylation occurs at least in part through the upstream β-adrenergic receptor. Mechanistically, NNK-induced Bad phosphorylation prevents its interaction with Bcl-XL. Because the specific depletion of PKCι by RNA interference inhibits both NNK-induced Bad phosphorylation and survival, this confirms that PKCι is a necessary component in NNK-mediated survival signaling. Collectively, these findings reveal a novel role for PKCι as an NNK-activated physiological Bad kinase that can directly phosphorylate and inactivate this proapoptotic BH3-only protein, which leads to enhanced survival and chemoresistance of human lung cancer cells.

CIS-diamminedichloroplatinum(II) inhibits p34cdc2 protein kinase in human lung-cancer cells

1993 ◽  
Vol 55 (4) ◽  
pp. 616-622 ◽  
Author(s):  
Kazuto Nishio ◽  
Yasuhiro Fujiwara ◽  
Yuki Miyahara ◽  
Yuichiro Takeda ◽  
Tatsuo Ohira ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Protein Kinase ◽  
Cancer Cells ◽  
Human Lung ◽  
Lung Cancer Cells ◽  
Human Lung Cancer ◽  
Human Lung Cancer Cells

scholarly journals KLF8 overexpression promotes the growth of human lung cancer cells by promoting the expression of JMJD2A

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Dongjie Ma ◽  
Hongsheng Liu ◽  
Yingzhi Qin ◽  
Zhenhuan Tian ◽  
Shanqing Li ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Cycle ◽  
Small Cell Lung Cancer ◽  
Cancer Cells ◽  
Colony Formation ◽  
Human Lung ◽  
Small Cell ◽  
Lung Cancer Cells ◽  
Human Lung Cancer ◽  
Small Cell Lung

Abstract Background Non-small-cell lung cancer (lung cancer) has become one of the leading causes worldwide and the underlying mechanism is not fully understood. The transcriptional factor Kruppel like factor 8 (KLF8) is involved in the initiation, progression, transformation, and metastasis of diverse cancers. However, the roles of KLF8 in human non-small cell lung cancer remain unknown. Methods CCK-8 kit and colony formation assay were performed to determine the cell growth of lung cancer cells. Flow cytometry analysis was used to evaluate apoptosis and cell cycle of lung cancer cells. Luciferase reporter assay was used to examine the activation of JMJD2A promoter by KLF8. Chromatin immunoprecipitation assay was performed to evaluate the binding of KLF8 to JMJD2A promoter. Western blot and polymerase chain reaction were applied to analyze the expression of interested genes. Results The mRNA and protein levels of KLF8 in human non-small cell lung cancer tissues were overexpressed compared with the non-cancer tissues. KLF8 was knocked down with lentivirus-mediated short-hairpin RNA (shRNA) in human lung cancer cells (A549 and H1299 cells). The phenotypic results showed that KLF8 knockdown decreased the proliferation rate and colony formation of lung cancer cells. By contrast, lentivirus-mediated KLF8 overexpression promoted the growth of lung cancer cells (A549 and H1299 cells) and non-cancerous bronchial epithelial cell line BEAS-2B. Next, we showed that KLF8 regulated cell cycle at the G0 phase but not regulates cellular apoptosis of lung cancer cells. KLF8 regulated the expression of the cell cycle regulators P21 and CDK4 in a JMJD2A-dependent manner and JMJD2A knockdown significantly blocked the functions of KLF8 in regulating cell cycle and proliferation of lung cancer cells. Finally, we observed that KLF8 bound the promoter of JMJD2A and facilitated the expression of JMJD2A. Conclusions Our evidence demonstrated that KLF8 upregulation in human lung cancer promotes the cell proliferation and colony formation of lung cancer cells. KLF8 binds to the promoter of JMJD2A and subsequently regulates the expression of P21 and CDK4, which contributes to the regulation of cell cycle by KLF8. KLF8 may serve as a target for the treatment of human lung cancer.

Sulindac enhances adenoviral vector expressing mda-7/IL-24–mediated apoptosis in human lung cancer

2020 ◽  
Author(s):  
Lungwani Muungo
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cancer Cells ◽  
Cell Lung Cancer ◽  
Half Life ◽  
Human Lung ◽  
Small Cell ◽  
Lung Cancer Cells ◽  
Human Lung Cancer ◽  
Small Cell Lung

Several studies have shown antitumor activities of themelanoma differentiation–associated gene 7 (mda-7) andthe nonsteroidal anti-inflammatory drug sulindac whenused as a monotherapies against a wide variety of humancancers. However, the combined effects of mda-7 andsulindac have not previously been tested. Therefore, wetested the antitumor activity of an adenoviral vectorexpressing mda-7 (Ad-mda7) in combination with sulindacagainst non–small cell lung cancer cells in vitro andin vivo. When treated with Ad-mda7 in combination withsulindac, human lung cancer cells (A549 and H1299)underwent growth suppression resulting in apoptosis. Thegrowth inhibition induced by Ad-mda7 in combination withsulindac was significantly greater than that observed withAd-mda7 or sulindac alone. Furthermore, the degree ofgrowth inhibition induced using this combination wasdose-dependent for sulindac. Treatment with Ad-mda7 incombination with sulindac had no growth inhibitoryeffects on human normal lung (CCD-16) fibroblasts. Wethen investigated the mechanism by which sulindacenhances Ad-mda7-mediated apoptosis. Sulindac increasedexpression of ectopic MDA-7 protein in tumorcells, thereby increasing the expression of downstreameffectors RNA-dependent protein kinase, p38MAPK,caspase-9, and caspase-3 and enhancing apoptosis ofnon–small cell lung cancer cells. Pulse-chase experimentsshowed that the increased expression of MDA-7 protein insulindac-treated cells was due to increased half-life of theMDA-7 protein. Finally, treatment of human lung tumorxenografts in nude mice with Ad-mda7 plus sulindacsignificantly suppressed growth (P = 0.001) comparedwith Ad-mda7 or sulindac alone. Our results show for thefirst time that combined treatment with Ad-mda7 plussulindac enhances growth inhibition and apoptosis ofhuman lung cancer cells. The increased antitumor activityobserved with the combination treatment is a result ofincreased half-life of MDA-7 protein. Regulation of proteinturnover is a heretofore-unrecognized mechanism of thisnonsteroidal anti-inflammatory drug. [Mol Cancer Ther2005;4(2):291–304]

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