Bcr-Abl induces autocrine IGF-1 signaling

Lakshmikuttyamma, Ashakumary; Pastural, Élodie; Takahashi, Naoto; Sawada, Ken; Sheridan, David P.; DeCoteau, John F.; Geyer, C. Ronald

doi:10.1038/onc.2008.8

Cited by 36 publications

(29 citation statements)

References 74 publications

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“…The discrepancy in IC 50 values for Aurora A between data generated at GlaxoSmithKline (Supplementary Table S1) and the KinaseProfiler screen (Supplementary Table S2) is likely due to the presence of the Aurora A accessory protein TPX2 in the GlaxoSmithKline assays. 3 Overall, these data suggest that GSK1904529A is a highly selective IGF-IR and IR inhibitor.…”

Section: Discussionmentioning

confidence: 99%

Antitumor Activity of GSK1904529A, a Small-molecule Inhibitor of the Insulin-like Growth Factor-I Receptor Tyrosine Kinase

Sabbatini

Rowand

Groy

et al. 2009

Clinical Cancer Research

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Purpose: Dysregulation of the insulin-like growth factor-I receptor (IGF-IR) signaling pathway has been implicated in the development of many types of tumors, including prostate, colon, breast, pancreatic, ovarian, and sarcomas. Agents that inhibit IGF-IR activity may be useful in treatment of patients with various cancers. Experimental Design: Kinase assays were used to identify a selective small-molecule inhibitor of IGF-IR activity. The effects of this compound on IGF-IR signaling, cell proliferation, and the cell cycle were determined using a panel of cell lines. Antitumor activity was evaluated in human tumor xenografts growing in athymic mice. Inhibition of IGF-IR and the closely related insulin receptor (IR) was measured in vivo, and the effect on glucose metabolism was evaluated. Results: GSK1904529A selectively inhibits IGF-IR and IR with IC 50 s of 27 and 25 nmol/L, respectively. GSK1904529A blocks receptor autophosphorylation and downstream signaling, leading to cell cycle arrest. It inhibits the proliferation of cell lines derived from solid and hematologic malignancies, with multiple myeloma and Ewing's sarcoma cell lines being most sensitive. Oral administration of GSK1904529A decreases the growth of human tumor xenografts in mice, consistent with a reduction of IGF-IR phosphorylation in tumors. Despite the potent inhibitory activity of GSK1904529A on IR in vitro and in vivo, minimal effects on blood glucose levels are observed in animals at doses that show significant antitumor activity. Conclusion: GSK1904529A is a promising candidate for therapeutic use in IGF-IR^dependent tumors.

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Section: Discussionmentioning

confidence: 99%

Antitumor Activity of GSK1904529A, a Small-molecule Inhibitor of the Insulin-like Growth Factor-I Receptor Tyrosine Kinase

Sabbatini

Rowand

Groy

et al. 2009

Clinical Cancer Research

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“…42 In these cells, knockdown of Sox6 leads to a modest induction of fetal hemoglobin, which is greatly increased by the combined knockdown of BCL11A, which suggests that although these 2 proteins cooperate to silence ␥-genes, BCL11A has a preeminent role. 15 We have shown here that Sox6 strongly stimulates the transcription (in absolute terms) of all globin genes normally expressed by K562 cells, including ␥-globin and ⑀-globin (supplemental Figure 2).…”

Section: Discussionmentioning

confidence: 99%

“…11,13,15,42,43 To gain insight into its role in human erythroid cells, we overexpressed Sox6 in the erythroleukemic cell line K562 and in primary erythroid cultures derived from cord blood purified CD34 ϩ cells. In both cell types, Sox6-enforced expression resulted in significant erythroid terminal maturation.…”

Section: Discussionmentioning

confidence: 99%

Sox6 enhances erythroid differentiation in human erythroid progenitors

Cantù

Ierardi

Alborelli

et al. 2011

Blood

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Sox6 belongs to the Sry (sex-determining region Y)-related high-mobility-groupbox family of transcription factors, which control cell-fate specification of many cell types. Here, we explored the role of Sox6 in human erythropoiesis by its overexpression both in the erythroleukemic K562 cell line and in primary erythroid cultures from human cord blood CD34 ؉ cells. Sox6 induced significant erythroid differentiation in both models. K562 cells underwent hemoglobinization and, despite their leukemic origin, died within 9 days after transduction; primary erythroid cultures accelerated their kinetics of erythroid maturation and increased the number of cells that reached the final enucleation step. Searching for direct Sox6 targets, we found SOCS3 (suppressor of cytokine signaling-3), a known mediator of cytokine response. Sox6 was bound in vitro and in vivo to an evolutionarily conserved regulatory SOCS3 element, which induced transcriptional activation. SOCS3 overexpression in K562 cells and in primary erythroid cells recapitulated the growth inhibition induced by Sox6, which demonstrates that SOCS3 is a relevant Sox6 effector. (Blood. 2011;117(13):3669-3679) IntroductionSox proteins are important transcriptional regulators of different developmental processes in which they control the specification and differentiation of many cell types. [1][2][3] In particular, Sox6, originally isolated from adult mouse testis, 4 is required for the development of the central nervous system, 5-7 for chondrogenesis, 8 and for cardiac and skeletal muscle formation. 9,10 Recently, Sox6 has been demonstrated to be crucial for definitive erythropoiesis, 11-15 a process in which committed progenitors progressively differentiate into burst-forming-unit erythroid cells and colonyforming-unit (CFU) erythroid cells, which in turn give rise to proerythroblasts and erythroblasts and finally to mature, enucleated red blood cells. These differentiation stages are accompanied by profound maturational changes: Within few cell divisions, in parallel with the accumulation of erythroid-specific markers (membrane proteins, enzymes required for the heme biosynthesis pathway, and globins), cells undergo chromatin condensation and enucleate. 16,17 This complex spectrum of maturational steps is controlled at the molecular level by the integration of extrinsic (growth factors; oxygen and iron availability) and intrinsic (growth factor receptors, signaling mediators, transcription factors) signals.Several transcription factors are essential for erythroid commitment and for differential globin gene expression during development; their absence is associated with a wide spectrum of phenotypes ranging from mild perturbation to death because of a complete failure of erythropoiesis. 18,19 Among them, Sox6 recently has been shown to stimulate erythroid cell survival, proliferation, and terminal maturation during definitive murine erythropoiesis. 11,12 Sox6-null mouse fetuses and pups are anemic and have defective red blood cells. Recently, Sox6 has been implicated...

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“…Subsequently, other potential routes of PI3K activation, including those through Grb2-Gab2, the adapter proteins Crkl and c-Cbl, and oncogenes such as Src, Ras, and insulin receptor substrate 1, have also been characterized (17,18). Recently, it has also been shown that Bcr-Abl can also promote PI3K activity through inducing autocrine insulin-like growth factor 1 signaling (23).…”

mentioning

confidence: 99%

The Forkhead Transcription Factor FOXO3a Increases Phosphoinositide-3 Kinase/Akt Activity in Drug-Resistant Leukemic Cells through Induction of PIK3CA Expression

Hui

Gomes

Constantinidou

et al. 2008

Molecular and Cellular Biology

142

115

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The phosphoinositide-3 kinase (PI3K)/Akt signal pathway plays a key role in the tumorigenesis of many cancers and in the subsequent development of drug resistance. Using the K562 chronic myelogenous leukemia (CML) cell line and the doxorubicin-resistant derivative lines KD30 and KD225 as models, we observed that enhanced PI3K/Akt activity and the acquisition of chemoresistance correlated unexpectedly with the increased expression and nuclear accumulation of FOXO3a. Moreover, we found that the induction of FOXO3a activity in naïve K562 cells was sufficient to enhance PI3K/Akt activity and to confer resistance to the cytotoxic effects of doxorubicin. Conversely, the knockdown of endogenous FOXO3a expression reduced PI3K/Akt activity and sensitized these cells to doxorubicin. Further chromatin immunoprecipitation and promoter mutation analyses demonstrated that FOXO3a regulates the expression of the PI3K catalytic subunit p110␣ through the activation of a promoter region proximal to a novel untranslated exon upstream from the reported transcription start site of the p110␣ gene PIK3CA. As was the case for FOXO3a, the expression or knockdown of p110␣ was sufficient to amplify or reduce PI3K/Akt activity, respectively. Thus, our results suggest that the chronic activation of FOXO3a by doxorubicin in CML cells can enhance survival through a feedback mechanism that involves enhanced p110␣ expression and hyperactivation of the PI3K/Akt pathway.Chemotherapy is widely used for the treatment of leukemia and other advanced or metastatic cancers. However, its efficacy is often hampered by the development of intrinsic or acquired multidrug resistance (MDR), characterized by simultaneous cross-resistance to anticancer drugs that differ in their chemical structures, modes of action, and cellular targets (35). An understanding of the mechanisms of MDR is important for the development of more effective therapies. At the cellular level, three general mechanisms confer MDR in cancer cells, including decreased hydrophilic drug uptake, increased hydrophobic drug efflux, and enhanced cell survival signals or mechanisms. The first one involves a decrease in the expression or activity of transporters that regulate the uptake of hydrophilic chemotherapeutic drugs, such as folate antagonists, nucleoside analogues, and cisplatin. The second mechanism entails an upregulation of transporters, resulting in an increased energy-dependent efflux of a wide variety of hydrophobic chemotherapeutic agents. Finally, cancer cells often counteract the cytotoxic effects of therapeutic agents by amplifying the activity of proliferation and survival signal pathways, by increasing DNA damage repair, or by altering drug metabolism.Phosphoinositide-3 kinases (PI3Ks) are a family of lipid kinases that serve as mediators of signals generated by many different activated growth factor receptors and adhesion molecules. The class IA PI3Ks are heterodimers composed of a p110 catalytic subunit and a p85 regulatory subunit (25). When activated by growth factors, the p...

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Bcr-Abl induces autocrine IGF-1 signaling

Cited by 36 publications

References 74 publications

Antitumor Activity of GSK1904529A, a Small-molecule Inhibitor of the Insulin-like Growth Factor-I Receptor Tyrosine Kinase

Antitumor Activity of GSK1904529A, a Small-molecule Inhibitor of the Insulin-like Growth Factor-I Receptor Tyrosine Kinase

Sox6 enhances erythroid differentiation in human erythroid progenitors

The Forkhead Transcription Factor FOXO3a Increases Phosphoinositide-3 Kinase/Akt Activity in Drug-Resistant Leukemic Cells through Induction of PIK3CA Expression

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