Insulin Receptor Substrate-1 Is an Important Mediator of Ovarian Cancer Cell Growth Suppression by All-trans Retinoic Acid

Abstract

There is a need to identify more effective drugs for the treatment of ovarian cancer as it is the leading cause of death among gynecologic tumors. All-trans retinoic acid (ATRA), a natural retinoid, arrests the growth of CA-OV3 ovarian carcinoma cells in G 0 -G 1 . Because the insulin-like growth factor-I receptor has been implicated in the proliferation of various tumors, we investigated its potential role in the suppression of ovarian cancer cell growth by ATRA. Our studies revealed that insulin receptor substrate-1 (IRS-1) protein levels decrease in CA-OV3 cells on ATRA treatment, whereas no differences in IRS-1 levels were seen in the ATRA-resistant SK-OV3 cells. Moreover, CA-OV3 clones overexpressing IRS-1 were growth inhibited less by ATRA, whereas SK-OV3 clones in which levels of IRS-1 were reduced by expression of antisense IRS-1 became sensitive to growth inhibition by ATRA treatment. Studies to determine the mechanism by which ATRA reduced IRS-1 expression showed that ATRA altered steady-state levels of IRS-1 mRNA and the stability of IRS-1 protein. Finally, the role of IRS-1 as a potential molecular target of ATRA in ovarian tumors was assessed by immunohistochemistry in an ovarian cancer tissue array. Compared with normal ovary, the majority of malignant epithelial ovarian tumors overexpressed IRS-1. Thus, there seems to be a correlation between IRS-1 expression and malignancy in ovarian tumors. Our results suggest that IRS-1 is in fact an important growth-regulatory molecule that can be a potential effective target for chemotherapeutic intervention with growth-suppressive agents, including retinoids. [Cancer Res 2007;67(19):9266-75]

Tumor immune escape by the loss of homeostatic chemokine expression

“…injections (1 mg per mouse) of neutralizing antibodies against mCCL27 (clone 68623, rat IgG2b; R&D Systems) or isotype control twice weekly. To determine treatment effects on the primary tumor, the tumor volume was determined by measuring each tumor in three dimensions twice weekly as described previously (30). About 28 days after tumor cell injection when the performance of tumor-bearing animals became poor, as defined by the onset of cachexia, animals were killed and autopsied.…”

Insulin Receptor Substrate-1 Suppresses Transforming Growth Factor-β1–Mediated Epithelial-Mesenchymal Transition

“…Activation or inactivation of IRS-1 is highly correlated with the phosphorylation or dephosphorylation of IRS-1 tyrosine residues. Decrease in the tyrosine phosphorylation or protein levels of IRS-1 was reportedly associated with growth arrest or apoptosis of cancer cells induced by certain stimuli (14)(15)(16)(17). The role of IRS-1 in tumor progression or metastasis has been extensively characterized in recent years.…”

Expression of Micro‐RNA‐145 is regulated by a highly conserved genomic sequence 3′ to the pre‐miR

“…32D cells are mouse myeloid cells precursors (diploid) that do not express IRS-1 and express low levels of IGF-IR (Valentinis et al, 2000). MCF-7 cells are human breast cancer cells (Del Rincon et al, 2004) and CAOV-3 cells are ovarian carcinoma cells, sensitive to all-trans-retinoic acid (ATRA) (Ravikumar et al, 2007). HCT116 cells and its Dicer Ex5 mutant have been described by Shi et al (2007).…”