Downregulation of the type 1 insulin-like growth factor receptor in mouse melanoma cells is associated with enhanced radiosensitivity and impaired activation of Atm kinase

Macaulay, Valentine M.; Salisbury, A. J.; Bohula, Erin A.; Playford, Martin P.; Smorodinsky, Nechama I.; Shiloh, Yosef

doi:10.1038/sj.onc.1204565

Cited by 120 publications

(99 citation statements)

References 72 publications

(67 reference statements)

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“…IGF1R antisense oligonucleotides have been shown to inhibit melanoma cell survival in vitro and growth of FO-1 melanoma xenografts in nude mice (Resnicoff et al, 1994); the B-RAF status of these cells is unknown. We have shown that antisense-mediated IGF1R downregulation causes tumor growth delay and enhances radiosensitivity of murine B16.F1 melanoma (Macaulay et al, 2001). These findings suggest that the IGF1R is an attractive target for melanoma treatment.…”

Section: Introductionmentioning

confidence: 75%

“…IGF1R targeting has been linked with enhancement of chemosensitivity in several tumor cell types including breast cancer and Ewing's sarcoma (Min et al, 2003;Benini et al, 2004). We have demonstrated previously that antisense or siRNA-induced IGF1R downregulation led to enhancement of sensitivity to DNA-damaging cytotoxic drugs and ionizing irradiation in human prostate cancer cells and murine melanoma (Macaulay et al, 2001;Rochester et al, 2005). Given the highly chemo-resistant nature of human melanomas, it was important to assess the effect of IGF1R gene silencing on sensitivity to cytotoxic drugs.…”

Section: Igf1r Knockdown Enhances Sensitivity To Cytotoxic Drugs Usedmentioning

confidence: 91%

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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: Introductionmentioning

confidence: 75%

Section: Igf1r Knockdown Enhances Sensitivity To Cytotoxic Drugs Usedmentioning

confidence: 91%

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

2006

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“…This represents a similar enhancement of radiosensitivity to the effect seen previously in murine melanoma cells following antisense-mediated IGF1R downregulation. 25 In those cells, we had also observed a defect in the activation of Atm, 25 a multifunctional serine-threonine kinase that plays a critical role in the initiation of cell cycle checkpoints and DNA repair pathways following induction of dsDNA breaks. 49 Mitoxantrone, etoposide, and ionizing radiation share the capacity to induce dsDNA breaks, and induce cell death by apoptosis.…”

Section: Igf1r Gene Silencing Enhances Sensitivity To Dna-damaging Agmentioning

confidence: 99%

“…However, these results are also compatible with a key role for the IGF1R in the cellular response to DNA damage, as we and others have reported. 25,26 This could indicate that the ability to chemosensitize by IGF1R gene silencing was related to attenuation of the DNA damage response, in addition to withdrawal of apoptosis protection. The ability to sensitize a chemoresistant tumor type offers hope for the future development of IGF1R targeting as treatment for patients with hormone-escaped prostate cancer.…”

Section: Igf1r Gene Silencing Enhances Sensitivity To Dna-damaging Agmentioning

confidence: 99%

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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

et al. 2004

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The type 1 insulin-like growth factor receptor (IGF1R) is overexpressed in prostate cancer, and mediates proliferation, motility, and survival. Many prostate cancers harbor inactivating PTEN mutations, enhancing Akt phosphorylation. This activates the principal antiapoptotic pathway downstream of the IGF1R, calling into question the value of IGF1R targeting in this tumor. The aim of the current study was to assess the effect of IGF1R gene silencing in prostate cancer cells that lack functional PTEN protein. In human DU145, LNCaP and PC3 prostate cancer cells, transfection with IGF1R small interfering RNA induced significant enhancement of apoptosis and inhibition of survival, not only in PTEN wild-type DU145 but also in PTEN mutant LNCaP and PC3. This was attributed to attenuation of IGF signaling via Akt, ERKs and p38. In both DU145 and PC3, IGF1R knockdown led to enhancement of sensitivity to mitoxantrone, etoposide, nitrogen mustard and ionizing radiation. There was no sensitization to paclitaxel or 5-fluorouracil, which do not damage DNA, suggesting that chemosensitization results from impairment of the DNA damage response, in addition to removal of apoptosis protection. These results support the concept of IGF1R targeting in prostate cancer, and indicate that PTEN loss does not render tumor cells refractory to this strategy.

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Signaling Networks in Cutaneous Melanoma Metastasis Identified by Complementary DNA Microarrays

Nambiar¹,

Mirmohammadsadegh²,

Doroudi³

et al. 2005

Arch Dermatol

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Downregulation of the type 1 insulin-like growth factor receptor in mouse melanoma cells is associated with enhanced radiosensitivity and impaired activation of Atm kinase

Cited by 120 publications

References 72 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

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

Signaling Networks in Cutaneous Melanoma Metastasis Identified by Complementary DNA Microarrays

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