Expression of the wild-type insulin-like growth factor II receptor gene suppresses growth and causes death in colorectal carcinoma cells

Abstract

The insulin-like growth factor II receptor (IGFIIR) has been implicated as a tumor suppressor gene in human malignancy. Frequent mutation, loss of heterozygosity, and microsatellite instability (MSI) directly aecting the IGFIIR gene have been reported in several primary human tumor types. However, to our knowledge, dynamic functional evidence of a growth-suppressive role for IGFIIR has not yet been provided. We identi®ed one MSI-positive colorectal carcinoma cell line, SW48, with monoallelic mutation in IGFIIR identical to that seen in primary colorectal carcinomas. A zinc-inducible construct containing the wild-type IGFIIR cDNA was stably transfected into SW48 cells. Growth rate and apoptosis were compared between zinc-treated, untreated, and untransfected cells. A twofold increase in IGFIIR protein expression was detected after zinc treatment in discrete clonal isolates of transfected SW48 cells. Moreover, zinc induction of exogenous wild-type IGFIIR expression reproducibly decreased growth rate and increased apoptosis. These data prove that wild-type IGFIIR functions as a growth suppressor gene in colorectal cancer cells and provide dynamic in vitro functional support for the hypothesis that IGFIIR is a human growth suppressor gene.

The mannose 6‐phosphate/insulin‐like growth factor II receptor restricts the tumourigenicity and invasiveness of squamous cell carcinoma cells

“…Using colorectal carcinoma cells, Souza et al have been the first to demonstrate that M6P/IGF2R overexpression can impede the proliferation of tumour cells. 26 For choriocarcinoma and breast tumour cells, the growth-suppressive capacity of M6P/ IGF2R has been also verified in vivo. [23][24][25] It is thought that the anti-proliferative activity of M6P/IGF2R in tumour cells is mainly due to its impact on IGF-II signalling.…”

“…22 Furthermore, M6P/IGF2R overexpression has been found to reduce the growth of cancer cells both in vitro and in vivo, [23][24][25] in some cases simultaneously promoting cell death. 26 Conversely, M6P/IGF2R downregulation by antisense or ribozyme approaches accelerates tumour cell proliferation and renders the cells more resistant to apoptotic stimuli. 27,28 However, these studies were all performed using receptor-positive cancer cell lines, with only one of them displaying a reduced M6P/ IGF2R content.…”

M6P/IGF2R is mutated in squamous cell carcinoma of the lung

“…Evidence to date suggests, however, that the M6P/ IGF2R is not involved in cell signaling (Korner et al, 1995); this function is mediated primarily by the insulin-like growth factor I receptor (IGFIR) and the insulin receptor isoform A (Czech et al, 1989;Frasca et al, 1999). The M6P/IGF2R has also been shown to be mutated in a number of human cancers, including those that develop in the liver, breast and colon (Jirtle et al, 1999b), and to suppress cancer cell growth (Kang et al, 1999;O'Gorman et al, 1999;Souza et al, 1999). These ®ndings are consistent with the M6P/ IGF2R functioning normally as a tumor suppressor.…”

Identification of cell surface and secreted proteins essential for tumor cell survival using a genetic suppressor element screen

“…In total 25 genes in this category were identified by two or more putative GSEs (Table 1). We have included in the study the insulin-like growth factor II receptor/mannose-6-phosphate receptor (IGF2R) gene (which yielded a single antisense putative GSE in our apoptosis screen) since it was previously shown to promote apoptosis in different cancer cell models (Souza et al, 1999;Chen et al, 2002).…”