Antineoplastic effect of rapamycin is potentiated by inhibition of IRS-1 signaling in prostate cancer cells xenografts

• Published in: Journal of cancer research and clinical oncology Vol. 134; no. 8; pp. 833 - 839
• Main Authors: Oliveira, Josenilson C., Souza, Kellen K., Dias, Marília M., Faria, Marcel C., Ropelle, Eduardo R., Flores, Marcelo B. S., Ueno, Mirian, Velloso, Lício A., Saad, Sara T., Saad, Mario J. A., Carvalheira, José B. C.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.08.2008; Springer; Springer Nature B.V
• Subjects: Adaptor Proteins, Signal Transducing - drug effects; Adaptor Proteins, Signal Transducing - metabolism; Animals; Antibiotics, Antineoplastic - pharmacology; Antineoplastic agents; Apoptosis - drug effects; Biological and medical sciences; Blotting, Western; Cancer Research; Cell Line, Tumor; Cell Proliferation - drug effects; Drug therapy; Enzyme Activation - drug effects; Enzyme Activation - physiology; Gynecology. Andrology. Obstetrics; Hematology; Humans; Inhibitor drugs; Insulin Receptor Substrate Proteins; Internal Medicine; Kinases; Male; Male genital diseases; Medical sciences; Medicine; Medicine & Public Health; Mice; Mice, SCID; Nephrology. Urinary tract diseases; Oncology; Original Paper; Pharmacology. Drug treatments; Phosphorylation - drug effects; Prostate cancer; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - metabolism; Protein Kinases - drug effects; Protein Kinases - metabolism; Signal transduction; Signal Transduction - drug effects; Sirolimus - pharmacology; Skin & tissue grafts; TOR Serine-Threonine Kinases; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland; Xenograft Model Antitumor Assays; Prostate neoplasms; Insulin receptor substrate 1; Rapamycin; Phosphatidylinositol 3-kinase; Protein kinases; Antineoplastic agent; Prostate tumor; Prostate disease; Sirolimus; Non-specific serine/threonine protein kinase; Transplantation; Heterotransplantation; Macrocycle; Insulin receptor substrate-1 gene; Signal transduction; Surgery; Graft; Protein synthesis inhibitor; Male genital diseases; Tumor cell; Urinary system disease; Enzyme; Transferases; Lactone; Malignant tumor; Macrolide; 1-Phosphatidylinositol 3-kinase; Treatment; Animal; Prostate cancer; Cancer
• ISSN: 0171-5216; 1432-1335
• DOI: 10.1007/s00432-008-0359-5

Proper activation of phosphoinositide 3-kinase-Akt pathway is critical for the prevention of tumorigenesis. Recent data have characterized a negative feedback loop, wherein mammalian target of rapamycin (mTOR) blocks additional activation of the Akt/mTOR pathway through inhibition insulin receptor substrate 1 (IRS-1) function. However, the potential of IRS-1 inhibition during rapamycin treatment has not been examined. Herein, we show that IRS-1 antisense oligonucleotide and rapamycin synergistically antagonize the activation of mTOR in vivo and induced tumor suppression, through inhibition of proliferation and induction of apoptosis, in prostate cancer cell xenografts. These data demonstrate that the addition of agents that blocks IRS-1 potentiate the effect of mTOR inhibition in the growth of prostate cancer cell xenografts.