ErbB4 localization to cardiac myocyte nuclei, and its role in myocyte DNA damage response

Icli, Basak; Bharti, Ajit; Pentassuglia, Laura; Peng, Xiao; Sawyer, Douglas B.

doi:10.1016/j.bbrc.2011.12.144

Cited by 20 publications

(19 citation statements)

References 42 publications

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“…Moreover, ErbB4 may play a role in DOX-induced myocardial DNA damage [45]. Our results showing that DOX causes a greater increase in ErbB4 than AN-152 may explain the lack of cardiotoxicity so far seen in preclinical and clinical studies with AEZS-108 [24, 25, 27].…”

Section: Discussionmentioning

confidence: 82%

Receptor-targeted therapy of human experimental urinary bladder cancers with cytotoxic LH-RH analog AN-152 (AEZS-108)

Szepesházi

Keller²,

Block

et al. 2012

Oncotarget

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Many bladder cancers progress to invasion with poor prognosis; new therapeutic methods are needed. We developed a cytotoxic LH-RH analog, AN-152 (AEZS-108) containing doxorubicin (DOX), for targeted therapy of cancers expressing LHRH receptors. We investigated the expression of LH-RH receptors in clinical bladder cancers and in HT-1376, J82, RT-4 and HT-1197 human bladder cancer lines. The effect of analog, AN-152, on growth of these tumor lines xenografted into nude mice was analyzed. Using molecular and functional assays, we also evaluated the differences between the effects of AN-152, and DOX alone. We demonstrated the expression of LH-RH receptors on 18 clinical bladder cancers by immunohistochemistry and on four human urinary bladder cancer lines HT-1376, J82, RT-4 and HT-1197 by Western blotting and binding assays. AN-152 powerfully inhibited growth of these bladder cancers in nude mice. AN-152 exerted greater effects than DOX and was less toxic. DOX activated strong multidrug resistance mechanisms in RT-4 and HT-1197 cancers, while AN-152 had no or less such effect. PCR assays and in vitro studies revealed differences in the action of AN-152 and DOX on the expression of genes involved in apoptosis. These results suggest that targeted cytotoxic LH-RH analog, AN-152 (AEZS-108), should be examined for treatment of patients with LH-RH receptor positive invasive bladder cancers.

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Section: Discussionmentioning

confidence: 82%

Receptor-targeted therapy of human experimental urinary bladder cancers with cytotoxic LH-RH analog AN-152 (AEZS-108)

Szepesházi

Keller²,

Block

et al. 2012

Oncotarget

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“…Our results demonstrate that ErbB2 localizes to the peri-nuclear area and ErbB4 localizes to the nucleus in cardiac myocytes of failing type 1 diabetic post-MI hearts, thereby confirming our Western blot analysis. Previous studies have demonstrated that the increased localization of ErbB4 to the nucleus in adult rat ventricular myocytes may be an indicator of cell stress response [23], a finding that has also been observed in other receptor tyrosine kinases [24]. Whether nuclear localization of ErbB receptors affects their availability and/or ability to bind NRG-1 ligands and thereby contribute to the obliteration of compensatory NRG-1/ErbB signaling in the diabetic heart after MI is equally important from a therapeutic standpoint and warrants further investigation.…”

Section: Discussionmentioning

confidence: 99%

Type 1 diabetes mellitus abrogates compensatory augmentation of myocardial neuregulin-1β/ErbB in response to myocardial infarction resulting in worsening heart failure

Odiete

Konik

Sawyer

et al. 2013

Cardiovasc Diabetol

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BackgroundDiabetes mellitus (DM) patients surviving myocardial infarction (MI) exhibit a substantially higher incidence of subsequent heart failure (HF). Neuregulin (NRG)-1 and erythroblastic leukemia viral oncogene homolog (ErbB) receptors have been shown to play a critical role in maintenance of cardiac function. However, whether myocardial NRG-1/ErbB is altered during post-MI HF associated with DM remains unknown. The aim of this study was to determine the impact of type 1 DM on the myocardial NRG-1/ErbB system following MI in relation to residual left ventricular (LV) function.MethodsType 1 DM was induced in rats via administration of streptozotocin (65 mg/kg, i.p.). Control rats were injected with citrate buffer (vehicle) only. Two weeks after induction of type 1 DM, MI was produced in DM and non-DM rats by ligation of the left coronary artery. Sham MI rats underwent the same surgical procedure with the exception that the left coronary artery was not ligated. At 4 weeks after surgery, residual in vivo LV function was assessed via echocardiography. Myocardial protein expression of NRG-1β, ErbB2 and ErbB4 receptors, and MDM2 (a downstream signaling pathway induced by NRG-1 that has been implicated in cell survival) was assessed in the remaining, viable LV myocardium by Western blotting. Changes in ErbB receptor localization in the surviving LV myocardium of diabetic and non-diabetic post-MI rats was determined using immunohistochemistry techniques.ResultsAt 4 weeks post-MI, echocardiography revealed that LV fractional shortening (FS) and LV ejection fraction (EF) were significantly lower in the DM + MI group compared to the MI group (LVFS: 17.9 ± 0.7 vs. 25.2 ± 2.2; LVEF: 35.5 ± 1.4 vs. 47.5 ± 3.5, respectively; P < 0.05), indicating an increased functional severity of HF among the DM + MI rats. Up-regulation of NRG-1β and ErbB2 protein expression in the MI group was abrogated in the DM + MI group concurrent with degradation of MDM2, a downstream negative regulator of p53. ErbB2 and ErbB4 receptors re-localized to cardiac myocyte nuclei in failing type 1 diabetic post-MI hearts.ConclusionsType 1 DM prevents compensatory up-regulation of myocardial NRG-1/ErbB after MI coincident with an increased severity of HF.

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“…Similar to other ERBB family members, ERBB4 has been identified in the nucleus of normal and cancer cells (147–149). Most notably, the intracellular domain (ICD) generated by γ-secretase-mediated cleavage of ERBB4, can translocate to the nucleus (150).…”

Section: 2 Her/erbb Familymentioning

confidence: 98%

The role of HER2, EGFR, and other receptor tyrosine kinases in breast cancer

Hsu

Hung

2016

Cancer Metastasis Rev

293

185

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Breast cancer affects approximately 1 in 8 women, and it is estimated that over 246,660 women in the United States will be diagnosed with breast cancer in 2016. Breast cancer mortality has decline over the last two decades due to early detection and improved treatment. Over the last few years, there is mounting evidence to demonstrate the prominent role of receptor tyrosine kinases (RTKs) in tumor initiation and progression, and targeted therapies against the RTKs have been developed, evaluated in clinical trials, and approved for many cancer types, including breast cancer. However, not all breast cancers are the same as evidenced by the multiple subtypes of the disease, with some more aggressive than others, showing differential treatment response to different types of drugs. Moreover, in addition to canonical signaling from the cell surface, many RTKs can be trafficked to various subcellular compartments, such as the multivesicular body and nucleus, where they carry out critical cellular functions, such as cell proliferation, DNA replication and repair, and therapeutic resistance. In this review, we provide a brief summary on the role of a selected number of RTKs in breast cancer and describe some mechanisms of resistance.

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ErbB4 localization to cardiac myocyte nuclei, and its role in myocyte DNA damage response

Cited by 20 publications

References 42 publications

Receptor-targeted therapy of human experimental urinary bladder cancers with cytotoxic LH-RH analog AN-152 (AEZS-108)

Receptor-targeted therapy of human experimental urinary bladder cancers with cytotoxic LH-RH analog AN-152 (AEZS-108)

Type 1 diabetes mellitus abrogates compensatory augmentation of myocardial neuregulin-1β/ErbB in response to myocardial infarction resulting in worsening heart failure

The role of HER2, EGFR, and other receptor tyrosine kinases in breast cancer

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