Ophiopogonin B-induced autophagy in non-small cell lung cancer cells via inhibition of the PI3K/Akt signaling pathway

Chen,Meijuan; Du,Yuhong; Qui,Min; Wang,Mingyan; Chen,Kejun; Huang,Zhenzhou; Jiang,Miao; Xiong,Fei; Chen,Jianping; Zhou,Jing; Jiang,Fengrong; Yin,Lian; Tang,Yuping; Ye,Lihong; Zhan,Zhen; Duan,Jin-Αo; Fu,Hai-Αn; Zhang,Xu

doi:10.3892/or.2012.2131

February 2013 Volume 29 Issue 2

Full Size Image

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

An International Open Access Journal Devoted to General Medicine.

February 2013 Volume 29 Issue 2

Full Size Image

Article Open Access

Ophiopogonin B-induced autophagy in non-small cell lung cancer cells via inhibition of the PI3K/Akt signaling pathway

Authors:
- Meijuan Chen
- Yuhong Du
- Min Qui
- Mingyan Wang
- Kejun Chen
- Zhenzhou Huang
- Miao Jiang
- Fei Xiong
- Jianping Chen
- Jing Zhou
- Fengrong Jiang
- Lian Yin
- Yuping Tang
- Lihong Ye
- Zhen Zhan
- Jin-Αo Duan
- Hai-Αn Fu
- Xu Zhang
View Affiliations / Copyright

Affiliations: The Pre-clinical Medicine College, Nanjing University of Chinese Medicine, Nanjing 210046, P.R. China, Department of Pharmacology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA, The Pharmacology College, Nanjing University of Chinese Medicine, Nanjing 210046, P.R. China, The First Clinical Medicine College, Nanjing University of Chinese Medicine, Nanjing 210046, P.R. China

Copyright: © Chen et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].
Pages: 430-436
|
Published online on: November 9, 2012

https://doi.org/10.3892/or.2012.2131
Expand metrics +

Abstract

Ophiopogonin B (OP-B) is a bioactive component of Radix Ophiopogon Japonicus, which is often used in Chinese traditional medicine to treat pulmonary disease. However, whether or not OP-B has any potential antitumor activity has not been reported. Here, we show that the non-small cell lung cancer (NSCLC) cell lines NCI-H157 and NCI-H460 treated with OP-B grow more slowly and accumulate vacuoles in their cytoplasm compared to untreated control cells. Flow cytometric analysis showed that the cells were arrested in G0/G1 phase. Nuclear morphology, Annexin-V/PI staining, and expression of cleaved caspase-3 all confirm that OP-B does not induce apoptosis. Instead, based on results from both transmission electron microscopy (TEM) and the expression of microtubule-associated protein 1 light chain 3-II (LC3-II), we determined that OP-B treatment induced autophagy in both cell lines. Next, we examined the PI3K/Akt/mTOR signaling pathway and found that OP-B inhibited phosphorylation of Akt (Ser473, Thr308) in NCI-H157 cells and also inhibited several key components of the pathway in NCI-H460 cells, such as p-Akt(Ser473, Thr308), p-p70S6K (Thr389). Additionally, insulin-mediated activation of the PI3K/Akt/mTOR pathway provides evidence that activation of this pathway may correlate with induction of autophagy in H460 cells. Therefore, OP-B is a prospective inhibitor of PI3K/Akt and may be used as an alternative compound to treat NSCLC.

View Figures

View References

1	Kroemer G and Levine B: Autophagic cell death: the story of a misnomer. Nat Rev Mol Cell Biol. 9:1004–1010. 2008. View Article : Google Scholar : PubMed/NCBI
2	Liang XH, Jackson S, Seaman M, et al: Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature. 402:672–676. 1999. View Article : Google Scholar : PubMed/NCBI
3	Mizushima N: Autophagy: process and function. Genes Dev. 21:2861–2873. 2007. View Article : Google Scholar
4	Baehrecke EH: Autophagy: dual roles in life and death? Nat Rev Mol Cell Biol. 6:505–510. 2005. View Article : Google Scholar : PubMed/NCBI
5	Levy JM and Thorburn A: Targeting autophagy during cancer therapy to improve clinical outcomes. Pharmacol Ther. 131:130–141. 2011. View Article : Google Scholar : PubMed/NCBI
6	West KA, Brognard J, Clark AS, et al: Rapid Akt activation by nicotine and a tobacco carcinogen modulates the phenotype of normal human airway epithelial cells. J Clin Invest. 111:81–90. 2003. View Article : Google Scholar : PubMed/NCBI
7	Khan N, Afaq F, Khusro FH, Mustafa Adhami V, Suh Y and Mukhtar H: Dual inhibition of phosphatidylinositol 3-kinase/Akt and mammalian target of rapamycin signaling in human nonsmall cell lung cancer cells by a dietary flavonoid fisetin. Int J Cancer. 130:1695–1705. 2012. View Article : Google Scholar : PubMed/NCBI
8	Jorissen RN, Walker F, Pouliot N, Garrett TP, Ward CW and Burgess AW: Epidermal growth factor receptor: mechanisms of activation and signalling. Exp Cell Res. 284:31–53. 2003. View Article : Google Scholar : PubMed/NCBI
9	Saiki S, Sasazawa Y, Imamichi Y, et al: Caffeine induces apoptosis by enhancement of autophagy via PI3K/Akt/mTOR/p70S6K inhibition. Autophagy. 7:176–187. 2011. View Article : Google Scholar : PubMed/NCBI
10	Codogno P and Meijer AJ: Autophagy and signaling: their role in cell survival and cell death. Cell Death Differ. 12(Suppl 2): 1509–1518. 2005. View Article : Google Scholar : PubMed/NCBI
11	Inoki K, Li Y, Xu T and Guan KL: Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev. 17:1829–1834. 2003. View Article : Google Scholar : PubMed/NCBI
12	Inoki K, Li Y, Zhu T, Wu J and Guan KL: TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol. 4:648–657. 2002. View Article : Google Scholar : PubMed/NCBI
13	Garami A, Zwartkruis FJ, Nobukuni T, et al: Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2. Mol Cell. 11:1457–1466. 2003. View Article : Google Scholar : PubMed/NCBI
14	Clarke PG: Developmental cell death: morphological diversity and multiple mechanisms. Anat Embryol. 181:195–213. 1990. View Article : Google Scholar : PubMed/NCBI
15	Fujiwara K, Iwado E, Mills GB, Sawaya R, Kondo S and Kondo Y: Akt inhibitor shows anticancer and radiosensitizing effects in malignant glioma cells by inducing autophagy. Int J Oncol. 31:753–760. 2007.PubMed/NCBI
16	Kabeya Y, Mizushima N, Ueno T, et al: LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J. 19:5720–5728. 2000. View Article : Google Scholar : PubMed/NCBI
17	Blommaart EF, Krause U, Schellens JP, Vreeling-Sindelarova H and Meijer AJ: The phosphatidylinositol 3-kinase inhibitors wortmannin and LY294002 inhibit autophagy in isolated rat hepatocytes. Eur J Biochem. 243:240–246. 1997. View Article : Google Scholar : PubMed/NCBI
18	Petiot A, Ogier-Denis E, Blommaart EF, Meijer AJ and Codogno P: Distinct classes of phosphatidylinositol 3′-kinases are involved in signaling pathways that control macroautophagy in HT-29 cells. J Biol Chem. 275:992–998. 2000.
19	Arico S, Petiot A, Bauvy C, et al: The tumor suppressor PTEN positively regulates macroautophagy by inhibiting the phosphatidylinositol 3-kinase/protein kinase B pathway. J Biol Chem. 276:35243–35246. 2001. View Article : Google Scholar : PubMed/NCBI
20	O’Reilly KE, Rojo F, She QB, et al: mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res. 66:1500–1508. 2006.PubMed/NCBI

Journals

International Journal of Molecular Medicine

International Journal of Oncology

Molecular Medicine Reports

Oncology Reports

Experimental and Therapeutic Medicine

Oncology Letters

Biomedical Reports

Molecular and Clinical Oncology

World Academy of Sciences Journal

International Journal of Functional Nutrition

International Journal of Epigenetics

Medicine International

Ophiopogonin B-induced autophagy in non-small cell lung cancer cells via inhibition of the PI3K/Akt signaling pathway

This article is mentioned in:

Abstract

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Related Articles