The Akt1/IL-6/STAT3 pathway regulates growth of lung tumor initiating cells.
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.
Dipartimento di Medicina Sperimentale e Clinica, Università Magna Graecia, Catanzaro, Italy.
Donatella
D
Malanga
Dipartimento di Medicina Sperimentale e Clinica, Università Magna Graecia, Catanzaro, Italy.|Biogem scarl, Istituto di Ricerche Genetiche, Ariano Irpino (Avellino), Italy.
Carmela
C
De Marco
Biogem scarl, Istituto di Ricerche Genetiche, Ariano Irpino (Avellino), Italy.
Ilaria
I
Guerriero
Biogem scarl, Istituto di Ricerche Genetiche, Ariano Irpino (Avellino), Italy.
Fabiana
F
Colelli
Biogem scarl, Istituto di Ricerche Genetiche, Ariano Irpino (Avellino), Italy.
Nicola
N
Rinaldo
Dipartimento di Medicina Sperimentale e Clinica, Università Magna Graecia, Catanzaro, Italy.|Biogem scarl, Istituto di Ricerche Genetiche, Ariano Irpino (Avellino), Italy.
Marianna
M
Scrima
Dipartimento di Scienze Mediche e Chirurgiche, Università Magna Graecia, Catanzaro, Italy.
Teresa
T
Mirante
IRCCS Istituto Nazionale Tumori Fondazione G. Pascale, Napoli, Italy.
Claudia
C
De Vitis
Biogem scarl, Istituto di Ricerche Genetiche, Ariano Irpino (Avellino), Italy.
Pietro
P
Zoppoli
Dipartimento di Medicina Sperimentale e Clinica, Università Magna Graecia, Catanzaro, Italy.|Dipartimento di Scienze e Tecnologie, Università del Sannio, Benevento, Italy.
Michele
M
Ceccarelli
Dipartimento di Medicina Sperimentale e Clinica, Università Magna Graecia, Catanzaro, Italy.|Biogem scarl, Istituto di Ricerche Genetiche, Ariano Irpino (Avellino), Italy.
Miriam
M
Riccardi
Dipartimento di Medicina e Chirurgia, Università di Salerno, Baronissi, Italy.
Maria
M
Ravo
Dipartimento di Medicina e Chirurgia, Università di Salerno, Baronissi, Italy.
Alessandro
A
Weisz
Dipartimento di Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università Federico II, Napoli, Italy.
Antonella
A
Federico
IRCCS Istituto Nazionale Tumori Fondazione G. Pascale, Napoli, Italy.
Renato
R
Franco
IRCCS Istituto Nazionale Tumori Fondazione G. Pascale, Napoli, Italy.
Gaetano
G
Rocco
Dipartimento di Medicina Clinica e Molecolare, Università di Roma "La Sapienza" Ospedale S. Andrea, Roma, Italy.
Rita
R
Mancini
Dipartimento di Scienze Mediche e Chirurgiche, Università Magna Graecia, Catanzaro, Italy.
Antonia
A
Rizzuto
Dipartimento di Scienze della Salute, Università Magna Graecia, Catanzaro, Italy.
Elio
E
Gulletta
IRCCS Istituto Nazionale Tumori Fondazione G. Pascale, Napoli, Italy.
Gennaro
G
Ciliberto
Dipartimento di Medicina Sperimentale e Clinica, Università Magna Graecia, Catanzaro, Italy.|Biogem scarl, Istituto di Ricerche Genetiche, Ariano Irpino (Avellino), Italy.
Giuseppe
G
Viglietto
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D047369:Chromatin Immunoprecipitation; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection
C508600:IL6 protein, human; D015850:Interleukin-6; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt
Akt1; IL-6; NSCLC; STAT3; tumor initiating cells