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DLC-1 induces mitochondrial apoptosis and epithelial mesenchymal transition arrest in nasopharyngeal carcinoma by targeting EGFR/Akt/NF-κB pathway

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Abstract

Loss of deleted in liver cancer-1 (DLC-1) can induce apoptosis and inhibit the mobility, migration and metastasis in several cancers. Previously, we revealed that ectopic expression of DLC-1 can suppress proliferation, mobility, migration and tumorigenesis in nasopharyngeal carcinoma (NPC). However, the molecular mechanisms accounting for the roles of DLC-1 in NPC are still obscure. In the present work, we attempted to study and uncover the mechanisms underlying the functions of DLC-1 in NPC. The apoptosis of 5-8F-DLC-1 cells, established previously, was analyzed by mitochondrial membrane potentials assay and flow cytometer analysis. And the antibodies involving pathways such as mitochondrial-associated apoptosis, epithelial mesenchymal transition and metastasis were applied to detect and compare the expression level of targeted proteins. The obvious apoptosis of 5-8F-DLC-1 cells was observed reflected by mitochondrial depolarization and lower ratio in cell viability. Subsequently, the activation of mitochondrial apoptosis was verified by the increased expressions of Bax, Apaf1, cleave-caspases and cleave-PARP, etc, and the decreased expressions of Bcl-2, Bcl-xL, Mcl-1, Survivin, etc, in 5-8F-DLC-1 cells. Then, the inhibited epithelial mesenchymal transition of 5-8F-DLC-1 cells was validated by upregulated expression of E-cadherin and downregulated expression of N-cadherin, Snail, Vimentin. Subsequently, downregulated expressions of proteins such as FAK, RhoA, ROCK1 and cdc25 related to cell adhesion and cytoskeleton organization were also observed. And expressions of MMPs were inhibited in 5-8F-DLC-1 cells. At last, the inhibited activity of EGFR/Akt/NF-κB axis was revealed by the decreased expressions of phosho-EGFR, phosho-Akt, phosho-p38MAPK, phosho-IKKα and phosho-p65. Here, we systematically explored the mechanisms underlying the negative roles of DLC-1 in NPC cells. For the first time, we confirmed that the ectopic expression DLC-1 can induce mitochondrial apoptosis, inhibit EMT and related processes by targeting the EGFR/Akt/NF-κB pathway, which, beyond all doubt, offered beneficial guidelines for other studies and laid a good foundation for its clinical applications ultimately.

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (81272972), National Basic Research Program of China (2010CB833605), Incubation Program for National Natural Science Funds for Distinguished Young Scholar of Central South University (2010QYZD006), Hunan Provincial Science and Technology Department (2012FJ4040), Open-End Fund for the Valuable and Precision Instruments of Central South University.

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The authors declare that they have no conflict of interest here.

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    Authors and Affiliations

    1. Cancer Research Institute, Collaborative Innovation Center for Cancer Medicine, Key Laboratory for Carcinogenesis of Chinese Ministry of Health, Central South University, Xiangya Road 110, Changsha, 410078, Hunan, People’s Republic of China

      Wei Huang, Jie Liu, Xiangling Feng, Huan Chen, Guoling Huang, Weidong Liu, Lei Wang, Wei Jia, Jiawen Chen & Caiping Ren

    2. School of Public Health, Central South University, Up Mayuanling Lane 238, Changsha, 410008, Hunan, People’s Republic of China

      Xiangling Feng

    3. Department of Pathology, Hunan Cancer Hospital, Xiangya Road 88, Changsha, 410078, Hunan, People’s Republic of China

      Liang Zeng

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    1. Wei Huang
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    Correspondence to Xiangling Feng or Caiping Ren.

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    Wei Huang and Jie Liu have contributed equally to this work.

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    Huang, W., Liu, J., Feng, X. et al. DLC-1 induces mitochondrial apoptosis and epithelial mesenchymal transition arrest in nasopharyngeal carcinoma by targeting EGFR/Akt/NF-κB pathway. Med Oncol 32, 115 (2015). https://doi.org/10.1007/s12032-015-0564-4

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