LZTS2 inhibits PI3K/AKT activation and radioresistance in nasopharyngeal carcinoma by interacting with p85

Shuangbing Xu; Yan Li; Yanwei Lu; Jing Huang; Jinghua Ren; Sheng Zhang; Zhongyuan Yin; Kai Huang; Gang Wu; Kunyu Yang

doi:10.1016/j.canlet.2018.01.067

LZTS2 inhibits PI3K/AKT activation and radioresistance in nasopharyngeal carcinoma by interacting with p85

Cancer Lett. 2018 Apr 28:420:38-48. doi: 10.1016/j.canlet.2018.01.067. Epub 2018 Jan 31.

Authors

Shuangbing Xu¹, Yan Li¹, Yanwei Lu¹, Jing Huang¹, Jinghua Ren¹, Sheng Zhang¹, Zhongyuan Yin¹, Kai Huang², Gang Wu¹, Kunyu Yang³

Affiliations

¹ Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
² Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
³ Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. Electronic address: yangkunyu@medmail.com.cn.

PMID: 29409973
DOI: 10.1016/j.canlet.2018.01.067

Abstract

Phosphoinositide 3-kinase (PI3K) activity is aberrantly activated in nasopharyngeal carcinoma. However, the underlying mechanisms remain unclear. Here, we found that Leucine zipper tumor suppressor 2 (LZTS2) was downregulated and predicted poor prognosis in nasopharyngeal carcinoma patients. Furthermore, we identified the PI3K subunit p85 as a novel LZTS2-interacting protein using an unbiased proteomics approach. Moreover, we demonstrated that LZTS2 competes with p110 for p85 binding and inhibits activation of the PI3K/AKT signaling pathway. Functionally, we showed that LZTS2 suppresses tumorigenesis and radioresistance in nasopharyngeal carcinoma in a p85-dependent manner. Taken together, our results not only provide understanding of the molecular mechanisms by which PI3K/AKT signaling is activated but also suggest that targeting the LZTS2/PI3K/AKT signaling axis is a promising therapeutic strategy for radiosensitization of nasopharyngeal carcinoma.

Keywords: LZTS2; Nasopharyngeal carcinoma; PI3K; Radioresistance; p85.

Publication types

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

MeSH terms

Animals
Cell Cycle Proteins / genetics*
Cell Cycle Proteins / metabolism*
Cell Line, Tumor
Class Ia Phosphatidylinositol 3-Kinase / metabolism*
DNA-Binding Proteins / genetics*
DNA-Binding Proteins / metabolism*
Down-Regulation
Gene Expression Regulation, Neoplastic
HEK293 Cells
Humans
Mice
Nasopharyngeal Carcinoma / genetics
Nasopharyngeal Carcinoma / metabolism
Nasopharyngeal Carcinoma / pathology*
Nasopharyngeal Carcinoma / radiotherapy
Nasopharyngeal Neoplasms / genetics
Nasopharyngeal Neoplasms / metabolism
Nasopharyngeal Neoplasms / pathology*
Nasopharyngeal Neoplasms / radiotherapy
Neoplasm Transplantation
Phosphatidylinositol 3-Kinases / metabolism
Prognosis
Proteomics
Proto-Oncogene Proteins c-akt / metabolism
Radiation Tolerance*
Signal Transduction
Survival Analysis
Tumor Suppressor Proteins / genetics*
Tumor Suppressor Proteins / metabolism*
Xenograft Model Antitumor Assays

Substances

Cell Cycle Proteins
DNA-Binding Proteins
LZTS2 protein, human
Tumor Suppressor Proteins
Phosphatidylinositol 3-Kinases
Class Ia Phosphatidylinositol 3-Kinase
Proto-Oncogene Proteins c-akt