N-acetylcysteine (NAC) downregulates type I insulin-like growth factor receptor (IGF-IR) and epidermal growth factor receptor (EGFR) on colorectal carcinoma cell lines – possible mechanism underlying NAC-mediated chemoprevention and chemotherapy

R. G. Kelly; K. Nally; G. C. O'Sullivan; F. Shanahan; J. O'Connell

doi:10.1055/s-2005-922889

Endoscopy, Inhaltsverzeichnis

N-acetylcysteine (NAC) downregulates type I insulin-like growth factor receptor (IGF-IR) and epidermal growth factor receptor (EGFR) on colorectal carcinoma cell lines – possible mechanism underlying NAC-mediated chemoprevention and chemotherapy

RG Kelly ¹^,²^,³, K Nally ¹^,², GC O'Sullivan ³, F Shanahan ¹^,², J O'Connell ¹^,²

¹Department of Medicine
²Alimentary Pharmabiotic Centre
³Cork Cancer Research Centre, National University of Ireland, Cork – University College Cork

Abstract

Aims: To determine the molecular mechanisms underlying the chemopreventive and chemotherapeutic effects of the thiol-containing antioxidant N-acetylcysteine (NAC).

Methods: We investigated the effect of NAC on type I insulin-like growth factor receptor (IGF-IR) and epidermal growth factor receptor (EGFR) expression on a panel of colorectal carcinoma cell lines. The impact of NAC on proliferation and resistance to apoptosis was determined, and we also examined the consequence of cellular p53 status on NAC-mediated modulation of IGF-IR and EGFR expression. The effect of H2O2 and a range of thiol and non-thiol containing antioxidants on IGF-IR and EGFR expression was explored.

Results: NAC downregulates IGF-IR and EGFR expression on a panel of colorectal carcinoma cell lines representative of the genetic diversity of colorectal cancer. This effect occurs in a dose- and time-dependent manner, both at the protein and transcriptional level. NAC inhibits proliferation and resistance to apoptosis in response to serum or growth factors. The decrease in IGF-IR and EGFR expression is independent of cellular p53 status. The antioxidant activity of NAC is necessary for the downregulation of EGFR but not IGF-IR.

Conclusions: NAC-mediated downregulation of IGF-IR and EGFR may explain the potent chemopreventive and chemotherapeutic effects of NAC on colorectal cancer.