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The combination of RAD001 and MK-2206 exerts synergistic cytotoxic effects against PTEN mutant gastric cancer cells: involvement of MAPK-dependent autophagic, but not apoptotic cell death pathway.
PLoS One 2014; 9(1):e85116Plos

Abstract

In the current study, we showed that the combination of mammalian target of rapamycin (mTOR) inhibitor RAD001 (everolimus) and Akt inhibitor MK-2206 exerted synergistic cytotoxic effects against low-phosphatase and tensin homolog (PTEN) gastric cancer cells (HGC-27 and SNU-601 lines). In HGC-27 cells, RAD001 and MK-2206 synergistically induced G1/S cell cycle arrest, growth inhibition, cell death but not apoptosis. RAD001 and MK-2206 synergistically induced light chain 3B (LC3B) and beclin-1 expression, two important autophagy indicators. Meanwhile, the autophagy inhibitor 3-methyladenine (3-MA) and chloroquine inhibited the cytotoxic effects by RAD001 and MK-2206, suggesting that autophagic, but not apoptotic cell death was important for the cytotoxic effects by the co-administration. We observed that the combination of RAD001 and MK-2206 exerted enhanced effects on Akt/mTOR inhibition, cyclin D1 down-regulation and ERK/MAPK(extracellular signal-regulated kinase/mitogen-activated protein kinases) activation. Intriguingly, MEK/ERK inhibitors PD98059 and U0126 suppressed RAD001 plus MK-2206-induced beclin-1 expression, autophagy induction and cytotoxicity in HGC-27 cells. In conclusion, these results suggested that the synergistic anti-gastric cancer cells ability by RAD001 and MK-2206 involves ERK-dependent autophagic cell death pathway.

Authors+Show Affiliations

Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, China.Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, China.Department of Interventional Radiology, Suzhou Hospital Affiliated to Nanjing Medical University, Suzhou, Jiangsu, China.Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, China.Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, China.Department of Gastric Cancer and Soft Tissue Sarcomas, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, China.Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, China.Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, China.Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, China.Institute of Neuroscience, Soochow University, Suzhou, Jiangsu, China.Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, China.Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, China.Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, China.Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, China.Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, China.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24416349

Citation

Ji, Dongmei, et al. "The Combination of RAD001 and MK-2206 Exerts Synergistic Cytotoxic Effects Against PTEN Mutant Gastric Cancer Cells: Involvement of MAPK-dependent Autophagic, but Not Apoptotic Cell Death Pathway." PloS One, vol. 9, no. 1, 2014, pp. e85116.
Ji D, Zhang Z, Cheng L, et al. The combination of RAD001 and MK-2206 exerts synergistic cytotoxic effects against PTEN mutant gastric cancer cells: involvement of MAPK-dependent autophagic, but not apoptotic cell death pathway. PLoS ONE. 2014;9(1):e85116.
Ji, D., Zhang, Z., Cheng, L., Chang, J., Wang, S., Zheng, B., ... Li, J. (2014). The combination of RAD001 and MK-2206 exerts synergistic cytotoxic effects against PTEN mutant gastric cancer cells: involvement of MAPK-dependent autophagic, but not apoptotic cell death pathway. PloS One, 9(1), pp. e85116. doi:10.1371/journal.pone.0085116.
Ji D, et al. The Combination of RAD001 and MK-2206 Exerts Synergistic Cytotoxic Effects Against PTEN Mutant Gastric Cancer Cells: Involvement of MAPK-dependent Autophagic, but Not Apoptotic Cell Death Pathway. PLoS ONE. 2014;9(1):e85116. PubMed PMID: 24416349.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The combination of RAD001 and MK-2206 exerts synergistic cytotoxic effects against PTEN mutant gastric cancer cells: involvement of MAPK-dependent autophagic, but not apoptotic cell death pathway. AU - Ji,Dongmei, AU - Zhang,Zhe, AU - Cheng,Lei, AU - Chang,Jinjia, AU - Wang,Shanshan, AU - Zheng,Biqiang, AU - Zheng,Rongliang, AU - Sun,Zuojun, AU - Wang,Chenchen, AU - Zhang,Zhiqing, AU - Liu,Rujiao, AU - Zhang,Xiaowei, AU - Liu,Xin, AU - Wang,Xiaofeng, AU - Li,Jin, Y1 - 2014/01/09/ PY - 2013/01/15/received PY - 2013/11/30/accepted PY - 2014/1/14/entrez PY - 2014/1/15/pubmed PY - 2014/9/3/medline SP - e85116 EP - e85116 JF - PloS one JO - PLoS ONE VL - 9 IS - 1 N2 - In the current study, we showed that the combination of mammalian target of rapamycin (mTOR) inhibitor RAD001 (everolimus) and Akt inhibitor MK-2206 exerted synergistic cytotoxic effects against low-phosphatase and tensin homolog (PTEN) gastric cancer cells (HGC-27 and SNU-601 lines). In HGC-27 cells, RAD001 and MK-2206 synergistically induced G1/S cell cycle arrest, growth inhibition, cell death but not apoptosis. RAD001 and MK-2206 synergistically induced light chain 3B (LC3B) and beclin-1 expression, two important autophagy indicators. Meanwhile, the autophagy inhibitor 3-methyladenine (3-MA) and chloroquine inhibited the cytotoxic effects by RAD001 and MK-2206, suggesting that autophagic, but not apoptotic cell death was important for the cytotoxic effects by the co-administration. We observed that the combination of RAD001 and MK-2206 exerted enhanced effects on Akt/mTOR inhibition, cyclin D1 down-regulation and ERK/MAPK(extracellular signal-regulated kinase/mitogen-activated protein kinases) activation. Intriguingly, MEK/ERK inhibitors PD98059 and U0126 suppressed RAD001 plus MK-2206-induced beclin-1 expression, autophagy induction and cytotoxicity in HGC-27 cells. In conclusion, these results suggested that the synergistic anti-gastric cancer cells ability by RAD001 and MK-2206 involves ERK-dependent autophagic cell death pathway. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/24416349/The_combination_of_RAD001_and_MK_2206_exerts_synergistic_cytotoxic_effects_against_PTEN_mutant_gastric_cancer_cells:_involvement_of_MAPK_dependent_autophagic_but_not_apoptotic_cell_death_pathway_ L2 - http://dx.plos.org/10.1371/journal.pone.0085116 DB - PRIME DP - Unbound Medicine ER -