Abstract
Accumulating evidence supports a role of the PI3K-AKT pathway in the regulation of cell motility, invasion and metastasis. AKT activation is known to promote metastasis, however under certain circumstances, it also shows an inhibitory activity on metastatic processes, and the cause of such conflicting results is largely unclear. Here we found that AKT1 is an important regulator of metastasis and down-regulation of its activity is associated with increased metastatic potential of A549 cells. Inhibition of AKT1 enhanced migration and invasion in KRAS- or EGFR-mutant non-small cell lung cancer (NSCLC) cells. The allosteric AKT inhibitor MK-2206 promoted metastasis of KRAS-mutated A549 cells in vivo. We next identified that the phosphorylation of Myristoylated alanine-rich C-kinase substrate (MARCKS) and LAMC2 protein level were increased with AKT1 inhibition, and MARCKS or LAMC2 knockdown abrogated migration and invasion induced by AKT1 inhibition. This study unravels an anti-metastatic role of AKT1 in the NSCLC cells with KRAS or EGFR mutations, and establishes an AKT1-MARCKS-LAMC2 feedback loop in this regulation.
Highlights
Lung cancer is the leading cause of cancer death[1, 2] and non-small cell lung cancer (NSCLC) accounts for 80–85% of the cases
We demonstrated that AKT1 inhibition promoted migration and invasion of NSCLC cells with KRAS or EGFR mutation in vitro, and the pan-AKT inhibitor MK-2206 promoted A549 metastasis in vivo
This assay includes a panel of antibodies against 114 cancer-associated proteins, including 88 phospho-proteins (Supplementary Table S2)[17], and we screened for proteins that were differentially expressed in the A549-R0, -R1, -R2 and -R3 cells
Summary
Lung cancer is the leading cause of cancer death[1, 2] and non-small cell lung cancer (NSCLC) accounts for 80–85% of the cases. Hyperactivation of PI3K-AKT signaling can be due to activation of receptor tyrosine kinases (RTKs) or alteration in the specific components within the pathway such as PIK3CA (PI3K catalytic subunit alpha) mutation or deletion of the tumor suppressor phosphatase and tensin homolog (PTEN)[5, 6]. Alteration in this pathway is known to be one of the mechanisms causal for drug resistance to EGFR inhibitors, for instance, PIK3CA E545K mutation or loss of PTEN7, 8. Of ablation of inositol polyphosphate 5-phosphatase PIPP13 Together, these results suggested that differences in genetic background might contribute to the paradoxical roles of AKT in cell migration, invasion and metastasis. Our results provide first-hand evidence that differences in the genetic background influences the role of AKT1 in tumor invasion and metastasis in NSCLC
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