Neural Wiskott-Aldrich syndrome protein (nWASP) is implicated in human lung cancer invasion

Abstract

Lung cancer is one of the most commonly diagnosed cancers with survival much lower in patients diagnosed with distal metastases. It is therefore imperative to identify pathways involved in lung cancer invasion and metastasis and to consider the therapeutic potential of agents that can interfere with these molecular pathways. This study examines nWASP expression in human lung cancer tissues and explores the effect of nWASP inhibition and knockdown on lung cancer cell behaviour.MethodsQPCR has been used to measure nWASP transcript expression in human lung cancer tissues. The effect of wiskostatin, an nWASP inhibitor, on A-549 and SK-MES-1 lung carcinoma cell growth, adhesion, migration and invasion was also examined using several in vitro functional assays, including ECIS, and immunofluorescence staining. The effect of nWASP knockdown using siRNA on particular behaviours of lung cancer cells was also examined.ResultsPatients with high levels of nWASP expression in tumour tissues have significantly lower survival rates. nWASP transcript levels were found to correlate with lymph node involvement (p = 0.042). nWASP inhibition and knockdown was shown to significantly impair lung cancer cell growth. nWASP inhibition also affected other cell behaviours, in SK-MES-1 invasion and A-549 cell motility, adhesion and migration. Paxillin and FAK activity are reduced in lung cancer cell lines following wiskostatin and nWASP knockdown as shown by immunofluorescence and western blot.ConclusionsThese findings highlight nWASP as an important potential therapeutic target in lung cancer invasion and demonstrate that inhibiting nWASP activity using the inhibitor wiskostatin can significantly alter cell behaviour in vitro.

N-WASP Control of LPAR1 Trafficking Establishes Response to Self-Generated LPA Gradients to Promote Pancreatic Cancer Cell Metastasis

“…High levels of N-WASP expression correlate with progression and/or poor outcome in human lung cancer (Frugtniet et al., 2017), PDAC (Guo et al., 2014), hepatocellular carcinoma (Jin et al., 2013), invasive breast ductal carcinoma (Yu et al., 2012), and esophageal squamous cell carcinoma (Wang et al., 2010). N-WASP was implicated in invasion and metastasis in a murine breast cancer model (Gligorijevic et al., 2012), but surprisingly, deletion of N-WASP in a murine model of colorectal cancer accelerated tumorigenesis (Morris et al., 2018).…”

Negative Regulation of p53-Induced Senescence by N-WASP Is Crucial for DMBA/TPA-Induced Skin Tumor Formation

“…Using a genetic model, we demonstrate that N-WASP function in keratinocytes is crucial for the formation of DMBA/TPAinduced skin tumors. Earlier, a role for N-WASP in cancer cell migration (18)(19)(20) and proliferation (20) was reported, but the mechanism underlying N-WASP-dependent growth regulation remained unclear. Our data suggest that N-WASP affects DMBA/ TPA-induced tumor formation by regulating cellular aging and senescence.…”

Phosphorylation of GMFγ by c-Abl coordinates lamellipodial and focal adhesion dynamics

“…This may explain the significant rescue of speed and directionality observed with expression of Y104D-GMF γ in migrating c-Abl KD cells. Clinically, reports have demonstrated that GMF γ , N-WASP, and c-Abl are all upregulated in several pathologies afflicted by enhanced cell migration, suggesting this signaling cascade may play a role 9, 39, 55, 61-64.…”