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Mol Cancer Res. 2014 Apr;12(4):622-35. doi: 10.1158/1541-7786.MCR-13-0487. Epub 2014 Jan 21.

Utilization of liquid chromatography mass spectrometry analyses to identify LKB1-APC interaction in modulating Wnt/β-catenin pathway of lung cancer cells.

Author information

1
Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan. khcheng@faculty.nsysu.edu.tw.

Abstract

STK11/LKB1, a serine/threonine protein kinase and tumor suppressor, is a key upstream kinase of adenine monophosphate-activated protein kinase, which is a kinase involved in controlling cell polarity and maintaining cellular energy homeostasis. LKB1 is mutated in a significant number of Peutz-Jeghers syndrome (PJS) cases and sporadic cancers, and is most frequently mutated in lung adenocarcinomas; however, little is known about how LKB1 is involved in lung cancer progression. In this study, immunoprecipitation-HPLC tandem mass spectrometry (IP-LC-MS/MS) was performed to identify novel proteins interacting with LKB1 in lung cancer. Interestingly, many LKB1-interacting proteins acquired from the LC-MS/MS approach were mapped, using MetaCore pathway analysis, to the cystic fibrosis transmembrane conductance regulator activation pathway. Moreover, it was determined that LKB1 directly interacts with APC, and this LKB1-APC interaction was further confirmed by reverse immunoprecipitation assays, but GSK3β was dispensable for the association of LKB1 and APC. Importantly, LKB1 binds to APC to suppress the Wnt/β-catenin signaling pathway, which is known to be involved in cell proliferation and migration. Subsequent analysis of the downstream targets of the Wnt/TCF pathway led to the identification of several Wnt-regulated genes, such as CD44, COX-2, survivin, and c-Myc, whose expression levels are downregulated by LKB1. In summary, these results demonstrate that LKB1 regulates the Wnt pathway through a direct interaction with APC to suppress the tumorigenic/metastatic potential of lung tumors.

IMPLICATIONS:

LKB1 status influences the molecular circuitry (Wnt/β-catenin pathway), cellular biology, and may serve as a potential therapeutic node in genetically defined subsets of lung cancer.

PMID:
24448687
DOI:
10.1158/1541-7786.MCR-13-0487
[Indexed for MEDLINE]
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