Herg1 channels modulate integrin signaling to trigger angiogenesis and tumor progression in colorectal cancer

Olivia Crociani, Francesca Zanieri, Serena Pillozzi, Elena Lastraioli, Matteo Stefanini, Antonella Fiore, Angelo Fortunato, Massimo D'Amico, Marika Masselli, Emanuele De Lorenzo, Luca Gasparoli, Martina Chiu, Ovidio Bussolati, Andrea Becchetti, Annarosa Arcangeli

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Abstract

Angiogenesis is a potential target for cancer therapy. We identified a novel signaling pathway that sustains angiogenesis and progression in colorectal cancer (CRC). This pathway is triggered by β 1 integrin-mediated adhesion and leads to VEGF-A secretion. The effect is modulated by the human ether-à-go-go related gene 1 (Herg1) K + channel. Herg1 recruits and activates PI3K and Akt. This in turn increases the Hypoxia Inducible Factor (HIF)-dependent transcription of VEGF-A and other tumour progression genes. This signaling pathway has novel features in that the integrin-and Herg1-dependent activation of HIF (i) is triggered in normoxia, especially after CRC cells have experienced a hypoxic stage, (ii) involves NF-kB and (iii) is counteracted by an active p53. Blocking Herg1 switches this pathway off also in vivo, by inhibiting cell growth, angiogenesis and metastatic spread. This suggests that non-cardiotoxic anti-Herg1 drugs might be a fruitful therapeutic strategy to prevent the failure of anti-VEGF therapy.

Original languageEnglish (US)
Article number3308
JournalScientific reports
Volume3
DOIs
StatePublished - Dec 6 2013

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Crociani, O., Zanieri, F., Pillozzi, S., Lastraioli, E., Stefanini, M., Fiore, A., Fortunato, A., D'Amico, M., Masselli, M., De Lorenzo, E., Gasparoli, L., Chiu, M., Bussolati, O., Becchetti, A., & Arcangeli, A. (2013). Herg1 channels modulate integrin signaling to trigger angiogenesis and tumor progression in colorectal cancer. Scientific reports, 3, [3308]. https://doi.org/10.1038/srep03308