Oncotarget

Research Papers:

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 Ciliberto and Giuseppe Viglietto

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Oncotarget. 2015; 6:42667-42686. https://doi.org/10.18632/oncotarget.5626

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Abstract

Donatella Malanga1, Carmela De Marco1,2, Ilaria Guerriero2, Fabiana Colelli2, Nicola Rinaldo2, Marianna Scrima1,2, Teresa Mirante3, Claudia De Vitis7, Pietro Zoppoli2, Michele Ceccarelli1,4, Miriam Riccardi1,2, Maria Ravo5, Alessandro Weisz5, Antonella Federico6, Renato Franco7, Gaetano Rocco7, Rita Mancini8, Antonia Rizzuto3, Elio Gulletta9, Gennaro Ciliberto7, Giuseppe Viglietto1,2

1Dipartimento di Medicina Sperimentale e Clinica, Università Magna Graecia, Catanzaro, Italy

2Biogem scarl, Istituto di Ricerche Genetiche, Ariano Irpino (Avellino), Italy

3Dipartimento di Scienze Mediche e Chirurgiche, Università Magna Graecia, Catanzaro, Italy

4Dipartimento di Scienze e Tecnologie, Università del Sannio, Benevento, Italy

5Dipartimento di Medicina e Chirurgia, Università di Salerno, Baronissi, Italy

6Dipartimento di Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università Federico II, Napoli, Italy

7IRCCS Istituto Nazionale Tumori Fondazione G. Pascale, Napoli, Italy

8Dipartimento di Medicina Clinica e Molecolare, Università di Roma “La Sapienza” Ospedale S. Andrea, Roma, Italy

9Dipartimento di Scienze della Salute, Università Magna Graecia, Catanzaro, Italy

Correspondence to:

Giuseppe Viglietto, e-mail: [email protected]

Keywords: NSCLC, tumor initiating cells, Akt1, IL-6, STAT3

Received: June 15, 2015     Accepted: September 09, 2015     Published: October 13, 2015

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.


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