The metastasis suppressor protein NM23-H1 modulates the PI3K-AKT axis through interaction with the p110α catalytic subunit

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.

Mechanically activated ion channel Piezo1 contributes to melanoma malignant progression through AKT/mTOR signaling

“…Numerous evidences indicates that AKT/mTOR signaling is frequently activated in most malignant cancers, and regulates tumor cell proliferation, adhesion, survival, migration and invasion. 2 , 15–17 In addition, AKT phosphorylation induces tumor cell migration and invasion through degradation of the MMPs-mediated matrix. 18 Therefore, we treated melanoma cells with Yoda1 (a Piezo1 activator) at 10 μM as the most effective concentration.…”

“…In 2019, an estimated 96,480 new melanoma cases and 7 230 melanoma deaths were occurred in the United States. 1 Melanoma is a highly aggressive tumor and exhibit early metastasis, 2 which is one of the reasons for poor clinical outcomes. 3 , 4 Therefore, there is an urgent need to unravel the molecular mechanisms of the malignant progression of melanoma, and provide a prospective therapeutic strategy.…”

Targeting Akt in cancer for precision therapy

“… [ 254 , 255 ] NPM1 mutation AML [ 257 ] NM23-H1 Breast cancer, melanoma, etc. [ 248 ] CBL mutation Myeloid neoplasmas [ 249 ] BTK mutation or deficiency Follicular lymphoma [ 253 ] GPS2 mutation Breast cancer, medulloblastoma [ 250 – 252 ] CDH1 mutation or deficiency Gastric cancer, breast cancer, prostate cancer, colorectal cancer, ovarian cancer, etc. [ 261 , 262 ] SMAD4 mutation Colorectal cancer, pancreatic cancer [ 269 , 270 ] GAB2 mutation or amplification Hematological malignancies, ovarian cancer, lung cancer, neuroblastoma, melanoma, breast cancer [ 264 – 268 ] …”

“…Whether some of these aberrant changes can serve as biomarkers to predict the sensitivity to Akt inhibitors remains to be determined in clinical setting. The metastasis suppressor NM23-H1 (NME1) interacts with the class I PI3K catalytic subunit p110α and then inhibits Akt activation [ 248 ]. It remains to know whether NM23-H1 mutation or deficiency renders cancer cells sensitive to Akt inhibitors.…”

The Complex Functions of the NME Family—A Matter of Location and Molecular Activity

“…Serafini et al (University of Bologna, Italy [ 36 ]) show that loss or downregulation of Awd results in a dose-dependent loss of Notch signaling and affects Drosphila Wingless signaling. In an alternative anti-metastatic signaling pathway, NME1 interacts with p110α, a catalytic subunit of phosphoinositide 3-kinase (PI3K), to inhibit downstream PI3K-Akt signaling by so far unclear mechanisms [ 37 ]. In case of metastasis suppression by NME4, a primary mechanism is likely the maintenance of a fused mitochondrial network via NME4-controlled, Opa1-dependent mitochondrial fusion [ 33 ], analogous to the NME1/2-controlled dynamin-dependent endocytosis.…”