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

Rochester, Mark; Riedemann, Johann; Hellawell, Giles; Brewster, Simon; Macaulay, Valentine M.

doi:10.1038/sj.cgt.7700775

Cited by 102 publications

(114 citation statements)

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“…An increase in ERK phosphorylation was observed 48 h posttransfection. This was similar to effects we previously observed following IGF1R knockdown in prostate cancer cells (Rochester et al, 2005) and may be related …”

Section: Resultssupporting

confidence: 91%

“…In CHL-1 melanoma cells, there was clear suppression of IGF1R protein levels 48 h after transfection with IGF1R siRNA at concentrations of 1 nM and above ( Figure 1a). IGF1R protein knockdown caused inhibition of Akt phosphorylation (Figure 1a), comparable with results we reported in breast and prostate cancer cells (Bohula et al, 2003b;Rochester et al, 2005); this was associated with dosedependent inhibition of survival (Figure 1b). There was no difference in survival between control-transfected and untreated or mock-transfected cultures (not shown), suggesting that siRNA transfection was not associated with nonspecific toxicity in these cells.…”

Section: Resultssupporting

confidence: 89%

“…The absence of functional PTEN was associated with basal Akt phosphorylation, but this pathway retained a degree of IGF-sensitivity, and its activity was inhibited by IGF1R knockdown. These findings suggest that IGF1R targeting remains effective in tumor cells with deregulated PI3K-Akt signaling (Rochester et al, 2005).…”

Section: Introductionmentioning

confidence: 76%

“…We previously investigated the effect of activation of the PI3K-Akt pathway on sensitivity to IGF1R targeting in human prostate cancer cells. IGF1R gene silencing was shown to induce significant survival inhibition and also sensitized to DNA-damaging cytotoxic drugs (Rochester et al, 2005). These effects were independent of the presence of wild-type (WT) PTEN, a tumor suppressor gene encoding a phosphatase that antagonizes the effects of PI3K (McMenamin et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

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Human melanoma cells expressing V600E B-RAF are susceptible to IGF1R targeting by small interfering RNAs

2006

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The type 1 insulin-like growth factor receptor (IGF1R) is overexpressed by malignant melanomas compared with benign naevi, and mediates proliferation, motility and protection from apoptosis. However, the utility of IGF1R targeting as anti-cancer therapy may be limited by activating mutations in downstream signaling intermediates. We previously showed that IGF1R knockdown blocked survival of prostate cancer cells in which Akt activation was deregulated by PTEN loss. The current study investigated effects of IGF1R targeting in cells harboring activating RAS-RAF mutations, found in 70-80% of human melanomas. We assembled a panel of eight human melanoma cell lines: two expressing wild-type (WT) B-RAF and N-RAS, two with activating N-RAS mutations and four harboring V600E B-RAF. We also generated isogenic cell populations overexpressing WT or V600E B-RAF. Cells expressing V600E B-RAF were relatively resistant to apoptosis. However, IGF1R gene silencing was capable of inducing significant inhibition of survival, enhancement of apoptosis, and Btwo-fold sensitization to cisplatin and temozolomide. These effects were independent of mutation status and were associated with reduced activation of Akt and also, unexpectedly, of ERKs. These results support development of IGF1R targeting as therapy for melanoma, regardless of the presence of activating mutations in the RAS-RAF pathway.

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Section: Resultssupporting

confidence: 91%

Section: Resultssupporting

confidence: 89%

Section: Introductionmentioning

confidence: 76%

Section: Introductionmentioning

confidence: 99%

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Human melanoma cells expressing V600E B-RAF are susceptible to IGF1R targeting by small interfering RNAs

2006

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“…Gene knockdown was confirmed by RT-PCR in each cell line. We also trypsinized HCT116 cells and re-seeded the same number of cells in culture dishes after transfection and subsequent incubation of cells, as previously described (Rochester et al, 2005). Similar results were observed in cell growth and colony numbers (data now shown).…”

Section: Dfna5 Has Tumor Suppressive Activity In Crc Cell Linessupporting

confidence: 59%

Aberrant promoter methylation and tumor suppressive activity of the DFNA5 gene in colorectal carcinoma

et al. 2008

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To identify novel methylated gene promoters, we compared differential RNA expression profiles of colorectal cancer (CRC) cell lines with or without treatment of 5-aza-2 0 -deoxycytidine (5-aza-dC). Out of 1776 genes that were initially 'absent (that is, silenced)' by gene expression array analysis, we selected 163 genes that were increased after 5-aza-dC treatment in at least two of three CRC cell lines. The microarray results were confirmed by Reverse Transcription-PCR, and CpG island of the gene promoters were amplified and sequenced for examination of cancer-specific methylation. Among the genes identified, the deafness, autosomal dominant 5 gene, DFNA5, promoter was found to be methylated in primary tumor tissues with high frequency (65%, 65/100). Quantitative methylation-specific PCR of DFNA5 clearly discriminated primary CRC tissues from normal colon tissues (3%, 3/100). The mRNA expression of DFNA5 in four of five colon cancer tissues was significantly downregulated as compared to normal tissues. Moreover, forced expression of full-length DFNA5 in CRC cell lines markedly decreased the cell growth and colony-forming ability whereas knockdown of DFNA5 increased cell growth in culture. Our data implicate DFNA5 as a novel tumor suppressor gene in CRC and a valuable molecular marker for human cancer.

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Suppression of homologous recombination sensitizes human tumor cells to IGF‐1R inhibition

Lodhia

Gao

Aleksic

et al. 2014

Intl Journal of Cancer

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Inhibition of type 1 IGF receptor (IGF-1R) sensitizes to DNA-damaging cancer treatments, and delays repair of DNA double strand breaks (DSBs) by non-homologous end-joining and homologous recombination (HR). In a recent screen for mediators of resistance to IGF-1R inhibitor AZ12253801, we identified RAD51, required for the strand invasion step of HR. These findings prompted us to test the hypothesis that IGF-1R-inhibited cells accumulate DSBs formed at endogenous DNA lesions, and depend on residual HR for their repair. Indeed, initial experiments showed time-dependent accumulation of cH2AX foci in IGF-1R -inhibited or -depleted prostate cancer cells. We then tested effects of suppressing HR, and found that RAD51 depletion enhanced AZ12253801 sensitivity in PTEN wild-type prostate cancer cells but not in cells lacking functional PTEN. Similar sensitization was induced in prostate cancer cells by depletion of BRCA2, required for RAD51 loading onto DNA, and in BRCA2 2/2 colorectal cancer cells, compared with isogenic BRCA21/2 cells. We also assessed chemical HR inhibitors, finding that RAD51inhibitor BO2 blocked RAD51 focus formation and sensitized to AZ12253801. Finally, we tested CDK1 inhibitor RO-3306, which impairs HR by inhibiting CDK1-mediated BRCA1 phosphorylation. R0-3306 suppressed RAD51 focus formation consistent with HR attenuation, and sensitized prostate cancer cells to IGF-1R inhibition, with 2.4-fold reduction in AZ12253801 GI 50 and 13-fold reduction in GI 80 . These data suggest that responses to IGF-1R inhibition are enhanced by genetic and chemical approaches to suppress HR, defining a population of cancers (PTEN wild-type, BRCA mutant) that may be intrinsically sensitive to IGF-1R inhibitory drugs.

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

Cited by 102 publications

References 46 publications

Human melanoma cells expressing V600E B-RAF are susceptible to IGF1R targeting by small interfering RNAs

Human melanoma cells expressing V600E B-RAF are susceptible to IGF1R targeting by small interfering RNAs

Aberrant promoter methylation and tumor suppressive activity of the DFNA5 gene in colorectal carcinoma

Suppression of homologous recombination sensitizes human tumor cells to IGF‐1R inhibition

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