Poly(ester amine)-mediated, Aerosol-delivered Akt1 Small Interfering RNA Suppresses Lung Tumorigenesis

Xu, Cheng-Xiong; Jere, Dhananjay; Jin, Hua; Chang, Simyung; Chung, Young Seob; Shin, Ji‐Young; Kim, Jieun; Park, Sung Jin; Lee, Yong-Hoon; Chae, C.; Lee, Kee Ho; Beck, George R.; Cho, Chong‐Su; Cho, Myung‐Haing

doi:10.1164/rccm.200707-1022oc

Cited by 97 publications

(65 citation statements)

References 57 publications

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“…In support of this, Akt1 shRNA delivery in nanoparticles prevented nascent urethane-induced lung tumor formation by 35% with just a 30% decrease in Akt1 (Jiang et al ., 2009). This treatment also decreased both lung tumor number and tumor size in the K-ras LA1 transgenic model (Xu et al ., 2008). The potential opposing roles of Akt1 and Akt3 in lung tumorigenesis suggest that development of non-selective Akt inhibitors may not be successful.…”

Section: Discussionmentioning

confidence: 96%

Akt1 deletion prevents lung tumorigenesis by mutant K-ras

et al. 2011

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K-ras mutations are associated with smoking-induced lung cancer and poor clinical outcomes. In mice, K-ras mutations are sufficient to induce lung tumors, which require phosphoinoside-3-kinase (PI3K) and further downstream, mammalian target of rapamycin (mTOR) activation. However, the roles of individual Akt isoforms that link PI3K and mTOR are unknown. Here, we show that deletion of Akt1 but not Akt2 or Akt3 prevents lung tumorigenesis in a tobacco carcinogen-induced model and a genetic model. Akt1 deletion prevented tumor initiation as well as tumor progression, coincident with decreased Akt signaling in tumor tissues. In contrast, deletion of Akt3 increased tumor multiplicity in the carcinogen model and increased tumor size in the genetic model. Fibroblasts lacking Akt1 are resistant to transformation by mutant K-ras and stimulation by epidermal growth factor. Human lung cancer cells with mutant K-ras and diminished Akt1 levels fail to grow in vivo. These data suggest that Akt1 is the primary Akt isoform activated by mutant K-ras in lung tumors, and that Akt3 may oppose Akt1 in lung tumorigenesis and lung tumor progression. Given that Akt inhibitors in clinical development as cancer therapeutics are not isoform selective, these studies support specific targeting of Akt1 to mitigate the effects of mutant K-ras in lung cancer.

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Section: Discussionmentioning

confidence: 96%

Akt1 deletion prevents lung tumorigenesis by mutant K-ras

et al. 2011

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“…Western blotting and immunohistochemical assays were performed as described previously (18). For immunofluorescence (IF) assays, cells were transfected with the indicated oligonucleotides.…”

Section: Immunoblotting and Rip-chip Assaymentioning

confidence: 99%

Decreased Expression of miR216a Contributes to Non–Small-Cell Lung Cancer Progression

Wang¹,

et al. 2014

Clinical Cancer Research

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Purpose: The aim of the present study is to investigate the role and mechanism of miR216a in non-smallcell lung cancer (NSCLC).Experimental Design: The expression of miR216a in NSCLC cell lines and from NSCLC patient specimens was measured by real-time qRT-PCR. The correlation between gene expression and patient survival was analyzed using Kaplan-Meier methods. The effects of miR216a on NSCLC cell growth and metastasis were examined both in vitro and in vivo by overexpressing or inhibiting miR216a. Finally, the effect of miR216a on chemoresistance was investigated by MTT assay and flow cytometry.Results: miR216a expression was downregulated in specimens from patients with NSCLC compared with corresponding nontumor lung tissues. Clinical data indicate that decreased miR216a expression is inversely correlated with cancer stage, metastasis, and poor survival in patients with NSCLC. Our data also show that overexpression of miR216a suppresses NSCLC cell growth and metastasis, and enhances cisplatin-induced cell growth inhibition and apoptosis. In contrast, inhibition of miR216a stimulates NSCLC cell growth and metastasis, and suppresses cisplatin-induced cell growth inhibition and apoptosis. Furthermore, we demonstrate that miR216a exerts its role by directly targeting eIF4B and ZEB1.Conclusion: Our findings suggest that miR216a is a cancer suppressor miRNA and that overexpression of miR216a is a novel NSCLC treatment strategy. In addition, our clinical data indicate that miR216a may be a useful biomarker for predicting NSCLC progression.

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“…The chemical structures of polymers for polymeric nanoparticles used in pulmonary delivery systems are shown Figure 2. 26,29,38,39,[54][55][56][57]59,61,69,70,74,75,[79][80][81][82][83][84][85][86][87][88][89][90][91][92][93] Due to their biocompatibility, surface modification capability, and sustained-release properties, polymeric nanoparticles are intensively studied using various important pulmonary drugs. These pulmonary drug include antiasthmatic drugs, 22,26 antituberculosis drugs, 38,39 pulmonary hypertension drugs, 29 and anticancer drugs.…”

Section: Drugs For Inhalationmentioning

confidence: 99%