Down-regulation of Insulin Receptor by Antibodies against the Type I Insulin-Like Growth Factor Receptor: Implications for Anti–Insulin-Like Growth Factor Therapy in Breast Cancer

Sachdev, Deepali; Singh, Rajeeva; Fujita‐Yamaguchi, Yoko; Yee, Douglas

doi:10.1158/0008-5472.can-05-3126

Cited by 106 publications

(86 citation statements)

References 47 publications

(45 reference statements)

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“…Thus, it is reasonable to consider that the antibodies to IGFs may have better specificity for tumors than antibodies to the IGF-IR. Second, IGF-IR has a homology with the insulin receptor; IGF-IR-blocking agents may cross-react with the insulin receptor and thus induce glucose intolerance (38)(39)(40)(41). However, because our antibodies do not cross-react with insulin in vitro, they are not expected to affect the blood glucose level.…”

Section: Discussionmentioning

confidence: 98%

Ligand-Specific Antibodies to Insulin-Like Growth Factors Suppress Intestinal Polyp Formation in Apc+/− Mice

Matsunaka

Miyamoto

Shitara

et al. 2010

Molecular Cancer Therapeutics

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Insulin-like growth factors (IGF-I and IGF-II) play important roles in intestinal tumorigenesis. To investigate the effectiveness of IGF-targeting strategies, we conducted an in vivo study using anti-mouse neutralizing antibodies IGF-I (KM3168) and IGF-II (KM1468). Six-and 10-week-old Apc +/− mice were given KM3168 and/or KM1468 i.p. at two doses (0.01 or 0.1 μg/g weight) once or twice weekly for 4 weeks. To clarify the source of IGFs in vivo, we evaluated the expression levels of IGFs in the liver, normal small intestine, and polyps of the small intestine of Apc +/− mice. The phosphorylation status of IGF signalrelated molecules was examined using immunostaining to understand the mechanism underlying the effects of IGF-neutralizing antibody. The plasma half-life was 168 for KM3168 and 85 hours for KM1468. In two lineages of Apc +/− mice (Apc 1309 and Apc Min/+ ), a low dose (0.01 μg/g weight) of KM3168 and KM1468 significantly reduced the number of polyps when given once and twice weekly, respectively. Combined administration of the effective dose of each antibody had an additive effect. The liver was the main source of IGF-I, whereas the polyps of the small intestine and normal small intestine were the main source of IGF-II. IGF-neutralizing antibodies decreased the phosphorylation of IGF type 1 receptor and inhibited the signal transduction of the Akt pathway. These results suggest that IGF-I and IGF-II play important roles in polyp formation in Apc +/− mice and that specific antibodies to IGF-I and IGF-II may be promising antitumor agents. Mol Cancer Ther; 9(2); 419-28. ©2010 AACR.

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Section: Discussionmentioning

confidence: 98%

Ligand-Specific Antibodies to Insulin-Like Growth Factors Suppress Intestinal Polyp Formation in Apc+/− Mice

Matsunaka

Miyamoto

Shitara

et al. 2010

Molecular Cancer Therapeutics

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“…Because of the importance of IR in glucose homeostasis, an ideal anti-IGF strategy would target both IGFIR and IR only in tumor cells. 40 Given the restricted expression profile of Reg IV in normal tissues seen by immunohistochemistry, [9][10][11][12][13][14][15][16][17][18] anti-Reg IV therapy might represent a way to target IR activation only in tumors.…”

Section: Cancer Cell Biologymentioning

confidence: 99%

Regenerating islet‐derived family member, 4 modulates multiple receptor tyrosine kinases and mediators of drug resistance in cancer

Vanderlaag¹,

Wang²,

Fayadat‐Dilman³

et al. 2011

Intl Journal of Cancer

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Regenerating islet‐derived family member, 4 (Reg IV) is a secreted protein and member of the C‐type lectin superfamily. Expression analyses have characterized Reg IV as a prognostic marker for certain cancers; however, the functional role of Reg IV in cancer, including downstream signaling, has only begun to be elucidated. To investigate the biological role of Reg IV in cancer, phosphorylation events were studied in cancer cell lines in the context of either Reg IV stimulation (HCT116 cells) or knockdown of endogenous Reg IV (PC3 and KM12 cells). In addition to the previously observed impact on epidermal growth factor receptor and Akt phosphorylation, we observed modulation in the phosphorylation of multiple additional receptor tyrosine kinases (RTKs), including insulin receptor, insulin‐like growth factor receptor as well as their downstream effectors, mitogen‐activated protein kinase and phosphatidylinositol‐3‐kinase pathways. Furthermore, knockdown of Reg IV impacted the ability of insulin and EGF to stimulate downstream tyrosine phosphorylation. Knockdown of Reg IV in cancer cell lines inhibited anchorage‐dependent and anchorage‐independent (both soft‐agar and spheroid assays) cell growth and induced cell cycle arrest. This was accompanied by upregulation of p21 and p27. Transiently silencing Reg IV in cancer cells induced apoptosis and downregulated Bcl‐2. Conversely, stimulation of HCT116 cells with recombinant Reg IV induced Bcl‐2. Hsp27, a molecule implicated in drug resistance, was similarly modulated by Reg IV. Consistent with our observations with Reg IV siRNA‐mediated knockdown, monoclonal antibodies directed against Reg IV inhibited PC3 and KM12 cell growth. Collectively, Reg IV plays an important role in cancer by modulation of key signaling molecules including Hsp27, Bcl‐2 and multiple RTKs.

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“…The expression levels of hybrid receptors have been found to be elevated in some types of cancer cells (19,20). Furthermore, an increased level of, specifically, IGF-IR/IR Ϫex11 has been reported in breast cancer cells (21,22). It is therefore important to determine whether there is a specificity difference between the two splice variants of the hybrid receptors with respect to insulin, IGF-I, and IGF-II binding.…”

Section: Most Mammalian Cells Express Both Insulin Receptor (Ir)mentioning

confidence: 99%

Hybrid Receptors Formed by Insulin Receptor (IR) and Insulin-like Growth Factor I Receptor (IGF-IR) Have Low Insulin and High IGF-1 Affinity Irrespective of the IR Splice Variant

Slaaby

Schäffer

Lautrup-Larsen

et al. 2006

Journal of Biological Chemistry

171

128

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Insulin receptor (IR) and insulin-like growth factor I receptor (IGF-IR) are both from the same subgroup of receptor tyrosine kinases that exist as covalently bound receptor dimers at the cell surface. For both IR and IGF-IR, the most described forms are homodimer receptors. However, hybrid receptors consisting of one-half IR and one-half IGF-IR are also present at the cell surface. Two splice variants of IR are expressed that enable formation of two isoforms of the IGF-IR/IR hybrid receptor. In this study, these two splice variants of hybrid receptors were studied with respect to binding affinities of insulin, insulin-like growth factor I (IGF-I), and insulin-like growth factor II (IGF-II). Unlike previously published data, in which semipurified receptors have been studied, we found that the two hybrid receptor splice variants had similar binding characteristics with respect to insulin, IGF-I, and IGF-II binding. We studied both semipurified and purified hybrid receptors. In all cases we found that IGF-I had at least 50-fold higher affinity than insulin, irrespective of the splice variant. The binding characteristics of insulin and IGF-I to both splice variants of the hybrid receptors were similar to classical homodimer IGF-IR.

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Down-regulation of Insulin Receptor by Antibodies against the Type I Insulin-Like Growth Factor Receptor: Implications for Anti–Insulin-Like Growth Factor Therapy in Breast Cancer

Cited by 106 publications

References 47 publications

Ligand-Specific Antibodies to Insulin-Like Growth Factors Suppress Intestinal Polyp Formation in Apc+/− Mice

Ligand-Specific Antibodies to Insulin-Like Growth Factors Suppress Intestinal Polyp Formation in Apc+/− Mice

Regenerating islet‐derived family member, 4 modulates multiple receptor tyrosine kinases and mediators of drug resistance in cancer

Hybrid Receptors Formed by Insulin Receptor (IR) and Insulin-like Growth Factor I Receptor (IGF-IR) Have Low Insulin and High IGF-1 Affinity Irrespective of the IR Splice Variant

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