This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Haimsohn, M. Articles by Geier, A. Search for Related Content PubMed PubMed Citation Articles by Haimsohn, M. Articles by Geier, A.

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.

This article has been cited by other articles:

				C. Myskiw, Y. Deschambault, K. Jefferies, R. He, and J. Cao Aurintricarboxylic Acid Inhibits the Early Stage of Vaccinia Virus Replication by Targeting both Cellular and Viral Factors J. Virol., March 15, 2007; 81(6): 3027 - 3032. [Abstract] [Full Text] [PDF]

				F. Liang, Z. Huang, S.-Y. Lee, J. Liang, M. I. Ivanov, A. Alonso, J. B. Bliska, D. S. Lawrence, T. Mustelin, and Z.-Y. Zhang Aurintricarboxylic Acid Blocks in Vitro and in Vivo Activity of YopH, an Essential Virulent Factor of Yersinia pestis, the Agent of Plague J. Biol. Chem., October 24, 2003; 278(43): 41734 - 41741. [Abstract] [Full Text] [PDF]