Gene expression profiles in cells transformed by overexpression of the IGF-I receptor

Loughran, Gary; Huigsloot, Merei; Kiely, Patrick A.; Smith, Loraine M.; Floyd, Suzanne; Ayllón, Verónica; O’Connor, Rosemary

doi:10.1038/sj.onc.1208772

Cited by 38 publications

(31 citation statements)

References 44 publications

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“…Numerous studies have demonstrated that the IGF-1R is overexpressed in multiple cancer types (Xie et al, 1999;Adams et al, 2000;All-Ericsson et al, 2002;Loughran et al, 2005). The elevated expression of IGF-1R in neoplastic cells combined with its crucial roles in malignant growth makes IGF-1R an attractive target in cancer therapy.…”

Section: Introductionmentioning

confidence: 99%

Picropodophyllin induces downregulation of the insulin-like growth factor 1 receptor: potential mechanistic involvement of Mdm2 and β-arrestin1

Vasilcanu

Rosengren

et al. 2007

Oncogene

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The insulin-like growth factor 1 receptor (IGF-1R) is crucial for growth and survival of malignant cells. Experience in targeting IGF-1R in cancer models has shown that strategies promoting downregulation of the receptor are much more efficient in inducing apoptosis than those inhibiting the IGF-1R activity. Recently, we found that the cyclolignan picropodophyllin (PPP) inhibits phosphorylation of IGF-1R and activation of downstream signaling without interfering with the highly homologous insulin receptor (IR). Furthermore, PPP treatment caused strong regression of tumor grafts and prolonged survival of animals with systemic tumor disease. Here we demonstrate that PPP also downregulates the IGF-1R, whereas the IR and several other receptors were not affected. PPP-induced IGF-1R downregulation required expression of the MDM2 E3 ligase, which recently was found to ubiquitinate and cause degradation of the IGF-1R. In addition knockdown of barrestin1, the adaptor molecule known to bridges MDM2 and IGF-1R, prevented downregulation of the receptor and significantly decreased PPP-induced cell death. All together these data suggest that PPP downregulates IGF-1R by interfering with the action of b-arrestin1/MDM2 as well as the achieved receptor downregulation contributes to the apoptotic effect of PPP.

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Section: Introductionmentioning

confidence: 99%

Picropodophyllin induces downregulation of the insulin-like growth factor 1 receptor: potential mechanistic involvement of Mdm2 and β-arrestin1

Vasilcanu

Rosengren

et al. 2007

Oncogene

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“…Here, we show that A12 treatment alone down-regulated TUBB and survivin expression, which may account for possible mechanisms of A12 augmenting the effect of docetaxel. Furthermore, TUBB is an IGF-IR -regulated gene that is involved with IGF-IR -mediated transformation (26). Of the four up-regulated genes, IGFBP3 has been shown to inhibit IGF ligand signaling as well as to induce apoptosis in prostate tumor cells in a ligand-dependent manner (27 -30).…”

Section: Resultsmentioning

confidence: 99%

Combined In vivo Effect of A12, a Type 1 Insulin-Like Growth Factor Receptor Antibody, and Docetaxel against Prostate Cancer Tumors

Haugk

Coleman

et al. 2006

Clinical Cancer Research

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Purpose: A human type 1 insulin-like growth factor receptor antibody (A12) has been shown to effectively inhibit human xenograft tumor growth, including androgen-dependent and androgen-independent prostate tumors. Docetaxel, either as a single agent or combined with others, has shown a survival benefit in prostate cancer patients. Based on these data, we investigated the combined in vivo effect of A12 and docetaxel on human androgen-independent and osseous prostate tumor growth. Experimental Design: To study human androgen-independent prostate cancer model, LuCaP35V tumors were implanted s.c. into castrated severe combined immunodeficient mice. When tumors reached about 100 mm 3 , animals were treated with vehicle control docetaxel (10 or 20 mg/kg) and docetaxel in combination with A12 (40 Ag/kg) for 4 weeks.To study human osseous prostate cancer model, LuCaP 23.1 tumors were implanted intratibiae. When serum prostate-specific antigen reached 5 to 10 ng/mL, treatments were initiated. Results: A12 markedly augmented the inhibition of docetaxel on tumor growth.When docetaxel is combined with A12, the inhibition of tumor growth continued after treatment cessation, which was associated with continued apoptosis and decreased proliferation of tumor cells. Gene expression profiles indicated that the posttreatment suppression of tumor growth may be due to enhanced negative regulation of cell cycle progression^and/or cell survival^associated genes, some of which have been shown to induce resistance to docetaxel. Conclusions: Our findings suggest that targeting type 1 insulin-like growth factor receptor can enhance the therapeutic effect of docetaxel on advanced prostate cancer. Our findings also suggest a potential mechanism to improve the treatment efficacy of docetaxel in prostate cancer.

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“…PBK expression is enhanced in many tumour cell lines compared with non-transformed cells and can be induced by IGF-I The PBK cDNA was isolated in a screen for genes whose expression is enhanced in fibroblasts transformed owing to overexpression of the IGF-IR (R þ ) compared to fibroblasts lacking the receptor (RÀ) (Loughran et al, 2005b). Previous reports have demonstrated that PBK levels are high in leukaemia and some tumour cell lines (Simons-Evelyn et al, 2001;Nandi et al, 2004).…”

Section: Resultsmentioning

confidence: 99%

PBK/TOPK promotes tumour cell proliferation through p38 MAPK activity and regulation of the DNA damage response

2006

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The contribution of the insulin-like growth-factor-I receptor (IGF-IR) to tumour progression is well documented. To identify new mediators of IGF-IR function in cancer, we recently isolated genes differentially expressed in cells overexpressing the IGF-IR. Among these was the serine/threonine kinase PBK/TOPK (PDZ-binding kinase/T-LAK cell-originated protein kinase), previously associated with highly proliferative cells and tissues. Here, we show that PBK is expressed at high levels in tumour cell lines compared with non-transformed cells. IGF-I could induce PBK expression only in transformed cells, whereas epidermal growth factor could induce PBK in non-transformed MCF-10A breast epithelial cells. Suppression of PBK expression using small interfering RNA did not prevent progression through the cell cycle, but caused decreased proliferation over time in culture, and reduced clonogenic growth in soft agarose. PBK knockdown impaired p38 activation after long-term stimulation with different growth factors and reduced DU145 cells motility. Suppressed PBK expression also resulted in an impaired response to DNA damage that was evident by the decreased generation of c-H2AX, increased DNA damage and decreased cell survival. Taken together, the data indicate that PBK is necessary for appropriate activation and function of the p38 pathway by growth factors. Thus, enhanced expression of PBK may facilitate tumour growth by mediating p38 activation and by helping cells to overcome DNA damage.

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Gene expression profiles in cells transformed by overexpression of the IGF-I receptor

Cited by 38 publications

References 44 publications

Picropodophyllin induces downregulation of the insulin-like growth factor 1 receptor: potential mechanistic involvement of Mdm2 and β-arrestin1

Picropodophyllin induces downregulation of the insulin-like growth factor 1 receptor: potential mechanistic involvement of Mdm2 and β-arrestin1

Combined In vivo Effect of A12, a Type 1 Insulin-Like Growth Factor Receptor Antibody, and Docetaxel against Prostate Cancer Tumors

PBK/TOPK promotes tumour cell proliferation through p38 MAPK activity and regulation of the DNA damage response

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