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

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

Research output: Contribution to journalArticle

26 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)42667-42686
Number of pages20
JournalOncotarget
Volume6
Issue number40
DOIs
Publication statusPublished - 2015
Externally publishedYes

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Keywords

  • Akt1
  • IL-6
  • NSCLC
  • STAT3
  • Tumor initiating cells

ASJC Scopus subject areas

  • Oncology

Cite this

Malanga, D., De Marco, C., Guerriero, I., Colelli, F., Rinaldo, N., Scrima, M., Mirante, T., De Vitis, C., Zoppoli, P., Ceccarelli, M., Riccardi, M., Ravo, M., Weisz, A., Federico, A., Franco, R., Rocco, G., Mancini, R., Rizzuto, A., Gulletta, E., ... Viglietto, G. (2015). The Akt1/IL-6/STAT3 pathway regulates growth of lung tumor initiating cells. Oncotarget, 6(40), 42667-42686. https://doi.org/10.18632/oncotarget.5626