IGF-I regulates redox status in breast cancer cells by activating the amino acid transport molecule xC−

摘要

Insulin-like growth factors (IGFs) stimulate cell growth in part by increasing amino acid uptake. xCT (SLC7A11) encodes the functional subunit of the cell surface transport system xC⁻ which mediates cystine uptake, a pivotal step in glutathione synthesis and cellular redox control. In this study, we show that IGF-I regulates cystine uptake and cellular redox status by activating the expression and function of xCT in estrogen receptor-positive (ER+) breast cancer cells by a mechanism that relies on the IGF receptor substrate-1 (IRS-1). Breast cancer cell proliferation mediated by IGF-I was suppressed by attenuating xCT expression or blocking xCT activity with the pharmacological inhibitor sulfasalazine (SASP). Notably, SASP sensitized breast cancer cells to inhibitors of the IGF-I receptor in a manner reversed by the ROS scavenger N-acetyl-L-cysteine. Thus, IGF-I promoted the proliferation of ER+ breast cancer cells by regulating xC⁻ transporter function to protect cancer cells from ROS in an IRS-1 dependent manner. Our findings suggest that inhibiting xC⁻ transporter function may synergize with modalities that target the IGF-I receptor to heighten their therapeutic effects.