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Aurintricarboxylic Acid Induces a Distinct Activation of the IGF-I Receptor Signaling within MDA-231 Cells

Institue of Endocrinology (M.H., A.K., H.K., A.G.), Sheba Medical Center, Tel Hashomer, 52621; and Faculty of Life Sciences (R.B.), Bar-Ilan University, Ramat Gan, 51905, Israel

Address all correspondence and requests for reprints to: Dr. Avraham Geier, Institute of Endocrinology, Sheba Medical Center, 52621 Tel Hashomer, Israel. E-mail: . geiera{at}bezeqint.net

Aurintricarboxylic acid (ATA), a polymeric carboxylated triphenylmethane derivate, prevents apoptotic death in a variety of cell systems. Recently, we have shown that the survival promoting effect of ATA is transduced via activation of the IGF-I receptor (IGF-IR) signaling pathway. In breast cancer MDA-231 cells exposed either to the protein synthesis inhibitors cycloheximide or ricin or to the anticancer drug adriamycin, we have found that ATA, but not IGF-1, is a powerful antiapoptotic agent. The purpose of this study was to compare the ability of ATA and IGF-I to activate the IGF-IR signaling cascade and to correlate this ability to their survival potency. MDA-231 cells were exposed to ATA or IGF-I, up to 7 h, and the dynamics of activation of the IGF-IR signaling cascade was evaluated. Our results show that: 1) The amount of tyrosine phosphorylated IGF-IR proteins was greater after exposure to ATA, compared with IGF-I. 2) Two phosphorylated IGF-IR ß-subunits (a 95-kDa and a 75-kDa) were induced after exposure to ATA, whereas IGF-1 induced only the 95-kDa form. Immunoprecipitation of both receptor forms by antibodies against the -subunit and against the carboxy terminus of the ß-subunit of the IGF-IR suggests that the 75-kDa form could be the ß-chain truncated at the amino terminus above the -ß disulphide bridges. 3) The ATA-activated IGF-IR forms underwent slow dephosphorylation, compared with a rapid dephosphorylation of the IGF-I activated receptor. 4) The insulin receptor substrate-1/2-associated PI3K, Shc proteins, and the kinases Akt and Erk1/2, downstream mediators of the antiapoptotic signaling by IGF-IR, were activated to a higher extent and for a longer time period by ATA, compared with IGF-I. Taken together, the sustained activation of the IGF-IR signaling pathway by ATA may explain its stronger antiapoptotic effect. We suggest that this enhanced activity, and the different susceptibility of the IGF-IR to certain proteases and phosphatases, may indicate a distinct conformation of the ATA-activated IGF-IR.

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