Abstract
The PI3K pathway is one of the most deregulated pathways in cancer, which is predominantly due to gain of function mutations or altered expression of the PI3KCA gene. This is codified by what is seen for the class I PI3K catalytic subunit p110α, a common feature of many cancers. The metastasis suppressor protein NM23-H1 (NME1), whose ability to suppress the metastasis activities of different tumors has been widely described and was previously reported to alter phosphatidylinositol signaling. Here, we show interaction of NM23-H1 with the p110α subunit and the functional consequence of this interaction. This interaction is predominantly localized at the plasma membrane with some signals seen in the cytoplasmic compartment. Analysis of NM23-H1 levels showed a negative correlation between NM23-H1 expression and Akt phosphorylation, the key marker of PI3K pathway activation. Investigating the functional consequence of this interaction using cell motility and clonogenicity assays showed that expression of NM23-H1 reversed the enhanced migration, invasion, adhesion, and filopodia structure formation in cells expressing the p110α catalytic subunit. A similar trend was seen in anchorage-independent assays. Notably, differential analyses using NM23-H1 mutants which lacked the enzymatic and metastasis suppressor activity, showed no detectable interaction between p110α and the NM23-H1 mutant proteins P96S, H118F, and S120G, as well as no dysregulation of the PI3K-AKT axis.
Highlights
Cancer progression is a dynamic process that reaches its peak with the formation of a metastatic clone at a different position from the primary site
NM23-H1 interacts with the p110α catalytic subunit of PI3K Previous studies have shown that NM23-H1 was associated with signaling activities that are linked to kinase activation at the cell membrane[11]
The PI3K pathway is a hallmark of cancer, and deregulation of the p110α kinase is sufficient for cellular transformation or cancer progression
Summary
Cancer progression is a dynamic process that reaches its peak with the formation of a metastatic clone at a different position from the primary site In this context, the NM23-H1 (NME1) gene was shown to be a negative “Master Regulator” of cancer cells motility. The NM23-H1 (NME1) gene was shown to be a negative “Master Regulator” of cancer cells motility This occurs either through multiple enzyme activities (nucleoside diphosphate kinase (NDPK), protein histidine kinase, and a serine/threonine-specific protein kinase 3′-5′ exonuclease activity), or through its extensive interactome, that negatively regulates signaling pathways which leads to Pennino et al Oncogenesis (2021)10:34 mutations showed a reduced hexameric and increased dimeric oligomerization compared to the wild type. This preliminary characterization of the interaction between NM23-H1 and the p110α kinase puts forward an interesting scenario towards understanding the complex mechanism that underlying the antimetastatic behavior of the NM23-H1 protein
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