Abstract
Mutations and deletions of the tumor suppressor LKB1 (STK11) are common in several malignancies, especially in non-small lung cancer cells (NSCLC). In that cell type, LKB1 inactivation coexists with mutations at other important cancer genes, including KRAS and TP53. The mutant LKB1 indirectly increases transcription of genes involved in metastasis, including COX-2. LKB1 directly activates AMPK decreasing mTOR activity and plays roles in several other processes such as cell metabolism, cell polarity, apoptosis and DNA damage via p53 interaction. Metformin, an antidiabetic drug, have shown antitumor effects, sensitizes cells in coadjuvant cisplatin treatment and acts in AMPK independent and dependent mechanisms. Thus, we propose the application of CRISPR/Cas9 system as genome editing tool to correct the LKB1 nonsense mutation and restore protein expression, providing new insights regarding cisplatin resistance, survival and metformin response in A549 lung cancer cells.
Highlights
LKB1 (STK11) regulates cell energy homeostasis, cell polarization, apoptosis and DNA damage via p53 regulation
Loss of LKB1 is frequent in lung cancer cells, appearing in 20-30% of nonsmall cell lung cancers (NSCLCs) and ranks as the 3rd most frequent mutated gene in lung adenocarcinoma, after p53 and Ras, characterized as a critical barrier to pulmonary tumorigenesis, controlling initiation, differentiation and metastasis3
Given the successful application of CRISPR/Cas-9 for gene editing and correction in cell cultures, the present study aims to employ the system to correct LKB1 gene and restore protein expression, improving metformin effects in LKB1-dependent suppression of mTOR pathway
Summary
LKB1 (STK11) regulates cell energy homeostasis, cell polarization, apoptosis and DNA damage via p53 regulation. LKB1dependent and AMPK-dependent suppression of the mTOR pathway is possibly the most potent antineoplastic effect of metformin, an antidiabetic drug, but several studies shows positive effects in cancer cells by LKB1AMPK-independent pathway1. Our previous data show that metformin can sensitizes A549 lung cancer cells after treatment with cisplatin (CDDP) while suppresses mTOR signaling.
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