IGF-I receptor signaling in a prostatic cancer cell line with a PTEN mutation

Abstract

LNCaP prostatic cancer cells are characterized by having a PTEN mutation, low levels of type 1 insulinlike growth factor receptor (IGF-IR) and no IRS-1, one of the major substrates of the IGF-IR. The absence of IRS-1, an activator of PI3-kinase, is compensated in these cells by the mutation in PTEN, an inhibitor of PI3-kinase. However, IGF-IR signaling in the absence of IRS-1 can cause cell di erentiation and growth arrest. We hypothesized that these three characteristics may not be unrelated, speci®cally that, together, they may favor the metastatic spread of prostatic cancer cells without decreasing their growth potential. In support of this hypothesis, we report here that: (1) IRS-1 expression increases cell adhesion and decreases cell motility; (2) over-expression of the IGF-IR, in the absence of IRS-1, causes growth arrest and (3) a combination of IGF-IR and IRS-1 restores the transformed phenotype of LNCaP cells. These ®ndings suggest a mechanism by which prostatic cancer cells can achieve metastatic potential without interfering with their growth potential.

Insulin-like growth factor-I signaling in human neuroblastoma cells

“…In addition, overexpression of IRS-1 increases cell adhesion and decreases cell motility in LNCaP prostatic cancer cells, a phenotype similar to S cells . Collectively, our results and those of others (Valentinis et al, 1999;Reiss et al, 2000;Meyer et al, 2001) support a pivotal role for IRS expression in determining different degrees of cancer cell motility and adherence.…”

Silencing of the IGF1R gene enhances sensitivity to DNA-damaging agents in both PTEN wild-type and mutant human prostate cancer

“…This study used human prostate cancer cells DU145 (androgen-independent), PC3 (androgen-independent) and LNCaP (androgen-sensitive, lacking IRS-1; 21 18,20 All cell lines were negative when tested for Mycoplasma infection. DU145 and LNCaP were cultured in RPMI-1640 and PC3 in Hams F12 all supplemented with 10% fetal calf serum unless otherwise stated.…”

“…19 Loss of functional PTEN protein ensures that there is deregulated activation of the Akt pathway for apoptosis protection, even in prostate cancer cells such as LNCaP that lack IRS-1. 20,21 Previously, we used antisense strategies to downregulate the IGF1R in androgen-independent DU145 human prostate cancer, showing moderately decreased survival and enhanced sensitivity to cisplatin. 22 However, the limited efficacy and nonspecific toxicity associated with phosphorothioate antisense oligonucleotides prevented the demonstration of any effect in other prostate cancer cells.…”

The contradictions of the insulin-like growth factor 1 receptor

“…However, contrary to expectations, IRS-1 expression in these cells markedly reduces cell motility, and this e ect is IGF-Iindependent . These e ects of IRS-1 have been interpreted by Reiss et al (2000) as a modality by which prostatic cancer cells could favor their metastatic spread without compromising their ability to grow. By simply extinguishing the expression of IRS-1, the cancer cells would decrease their attachment to substrata and increase motility, thus favoring invasion and metastasis.…”

“…The loss of the mitogenic stimulus of IRS-1 (White, 1998;Peruzzi et al, 1999) would be compensated by the PTEN mutation, which restores the activity of the PI3-kinase pathway. Indeed, Akt, a downstream target of PI-3 kinase (reviewed in Chan et al, 1999), is constitutively activated in the parental LNCaP cells (Carson et al, 1998;Davies et al, 1999;Tamura et al, 1999;Reiss et al, 2000). If this interpretation is correct, then IRS-1 has also its contradictions.…”