The Akt1/IL-6/STAT3 pathway regulates growth of lung tumor initiating cells.

Alessandro Weisz,Gennaro Ciliberto,Elio Gulletta,Antonella Federico,Rita Mancini,Teresa Mirante,Miriam Riccardi,Marianna Scrima,Carmela De Marco,Giuseppe Viglietto,Ilaria Guerriero,Fabiana Colelli,Maria Ravo,Nicola Rinaldo,Pietro Zoppoli,Michele Ceccarelli,Gaetano Rocco,Renato Franco,Claudia De Vitis,Antonia Rizzuto,Donatella Malanga

doi:10.18632/oncotarget.5626

Abstract

Here we report that the PI3K/Akt1/IL-6/STAT3 signalling pathway regulates generation and stem cell-like properties of Non-Small Cell Lung Cancer (NSCLC) tumor initiating cells (TICs). Mutant Akt1, mutant PIK3CA or PTEN loss enhances formation of lung cancer spheroids (LCS), self-renewal, expression of stemness markers and tumorigenic potential of human immortalized bronchial cells (BEAS-2B) whereas Akt inhibition suppresses these activities in established (NCI-H460) and primary NSCLC cells. Matched microarray analysis of Akt1-interfered cells and LCSs identified IL-6 as a critical target of Akt signalling in NSCLC TICs. Accordingly, suppression of Akt in NSCLC cells decreases IL-6 levels, phosphorylation of IkK and IkB, NF-kB transcriptional activity, phosphorylation and transcriptional activity of STAT3 whereas active Akt1 up-regulates them. Exposure of LCSs isolated from NSCLC cells to blocking anti-IL-6 mAbs, shRNA to IL-6 receptor or to STAT3 markedly reduces the capability to generate LCSs, to self-renew and to form tumors, whereas administration of IL-6 to Akt-interfered cells restores the capability to generate LCSs. Finally, immunohistochemical studies in NSCLC patients demonstrated a positive correlative trend between activated Akt, IL-6 expression and STAT3 phosphorylation (n = 94; p < 0.05). In conclusion, our data indicate that aberrant Akt signalling contributes to maintaining stemness in lung cancer TICs through a NF-kB/IL-6/STAT3 pathway and provide novel potential therapeutic targets for eliminating these malignant cells in NSCLC.

Highlights

Lung cancer is the leading causes of cancer-related mortality worldwide, with a 5-year survival rate of only 15% for Non-Small Cell Lung Cancer (NSCLC) [1]
These results indicate that aberrant signalling through the phosphatidylinositol 3-kinase (PI3K) pathway – induced by mutant Akt1, PIK3CA or by PTEN loss - significantly increases the percentage of cells able to initiate in vitro growth as spheroids enriched in Tumour initiating cells (TICs) that efficiently support tumor growth in vivo
TICs isolated from NSCLCs are defined functionally for their ability to grow as spheres in vitro and for their tumorigenic potential in vivo [5, 6, 8, 9]

Summary

Introduction

Lung cancer is the leading causes of cancer-related mortality worldwide, with a 5-year survival rate of only 15% for NSCLC [1]. One of the main causes of disease relapse is the emergence of cancer cells resistant to therapy. This phenomenon has been attributed to a population of cells endowed with tumour-initiating potential that support the growth of NSCLC [2,3,4]. These cells, known as Tumour initiating cells (TICs), www.impactjournals.com/oncotarget have a high capacity for self-renewal and multi-lineage differentiation and are believed to be responsible for tumor development, recurrence and dissemination as well as the acquisition of drug resistance [3]. The sustained activation of the EGFR/SRC/ Akt signaling has been implicated in the regulation of self-renewal, growth and expansion of the side population compartment of NSCLC cells [13]

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Results

Conclusion