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1.
Future Med Chem ; 4(7): 927-35, 2012 May.
Article in English | MEDLINE | ID: mdl-22571616

ABSTRACT

Heat shock proteins (Hsps) are highly conserved proteins working as molecular chaperones for several cellular proteins essential for normal cell viability and growth, and have numerous cytoprotective roles. The expression of Hsps is induced in response to a wide variety of physiological and environmental stress insults, including anticancer chemotherapy, thus allowing the cell to survive lethal conditions. Cancer cells experience high levels of proteotoxic stress and rely upon stress-response pathways for survival and proliferation, thereby becoming dependent on proteins such as stress-inducible Hsps. Owing to the implication of Hsps in cancer, Hsp inhibition has recently emerged as an interesting potential anticancer strategy. Many natural and synthetic Hsp inhibitors molecular compounds are in development and many are being evaluated as potential cancer therapies. One of the Hsps in particular, Hsp90, has several client proteins and is emerging as a particularly exciting cancer target due to the prospect of simultaneously inhibiting chaperoning of numerous oncogenic proteins. This review describes the function of Hsps focusing on current efforts in exploiting the attributes of Hsps as potential targets for anticancer therapy.


Subject(s)
Antineoplastic Agents/therapeutic use , Heat-Shock Proteins/metabolism , Molecular Targeted Therapy/methods , Neoplasms/drug therapy , Neoplasms/metabolism , Animals , Antineoplastic Agents/pharmacology , Drug Discovery/methods , Gene Expression Regulation, Neoplastic/drug effects , Heat-Shock Proteins/antagonists & inhibitors , Heat-Shock Proteins/genetics , Humans , Neoplasms/genetics
2.
Oncogene ; 31(15): 1923-37, 2012 Apr 12.
Article in English | MEDLINE | ID: mdl-21874045

ABSTRACT

Radiation therapy remains the standard of care for many cancers, including the malignant pediatric brain tumor medulloblastoma. Radiation leads to long-term side effects, whereas radioresistance contributes to tumor recurrence. Radio-resistant medulloblastoma cells occupy the perivascular niche. They express Yes-associated protein (YAP), a Sonic hedgehog (Shh) target markedly elevated in Shh-driven medulloblastomas. Here we report that YAP accelerates tumor growth and confers radioresistance, promoting ongoing proliferation after radiation. YAP activity enables cells to enter mitosis with un-repaired DNA through driving insulin-like growth factor 2 (IGF2) expression and Akt activation, resulting in ATM/Chk2 inactivation and abrogation of cell cycle checkpoints. Our results establish a central role for YAP in counteracting radiation-based therapies and driving genomic instability, and indicate the YAP/IGF2/Akt axis as a therapeutic target in medulloblastoma.


Subject(s)
Cerebellar Neoplasms/genetics , Genomic Instability , Insulin-Like Growth Factor II/metabolism , Medulloblastoma/genetics , Medulloblastoma/radiotherapy , Nuclear Proteins/physiology , Proto-Oncogene Proteins c-akt/metabolism , Transcription Factors/physiology , Animals , Cell Cycle Checkpoints , Cell Cycle Proteins , Cerebellar Neoplasms/radiotherapy , DNA Damage , Humans , Mice , Mice, Transgenic , Radiation Tolerance
3.
Oncogene ; 30(4): 410-22, 2011 Jan 27.
Article in English | MEDLINE | ID: mdl-20890301

ABSTRACT

Deregulation of the Rb/E2F tumor suppressor complex and aberrantion of Sonic hedgehog (Shh) signaling are documented across the spectrum of human malignancies. Exaggerated de novo lipid synthesis is also found in certain highly proliferative, aggressive tumors. Here, we show that in Shh-driven medulloblastomas, Rb is inactivated and E2F1 is upregulated, promoting lipogenesis. Extensive lipid accumulation and elevated levels of the lipogenic enzyme fatty acid synthase (FASN) mark those tumors. In primary cerebellar granule neuron precursors (CGNPs), proposed Shh-associated medulloblastoma cells-of-origin, Shh signaling triggers E2F1 and FASN expression, whereas suppressing fatty acid oxidation (FAO), in a smoothened-dependent manner. In the developing cerebellum, E2F1 and FASN co-localize in proliferating CGNPs. in vivo and in vitro, E2F1 is required for FASN expression and CGNP proliferation, and E2F1 knockdown impairs Shh-mediated FAO inhibition. Pharmacological blockade of Rb inactivation and/or lipogenesis inhibits CGNP proliferation, drives medulloblastoma cell death and extends survival of medulloblastoma-bearing animals In vivo. These findings identify a novel mechanism through which Shh signaling links cell cycle progression to lipid synthesis, through E2F1-dependent regulation of lipogenic enzymes. These findings pertinent to the etiology of tumor metabolism also underscore the key role of the Shh→E2F1→FASN axis in regulating de novo lipid synthesis in cancers, and as such its value as a global therapeutic target in hedgehog-dependent and/or Rb-inactivated tumors.


Subject(s)
Cerebellar Neoplasms/metabolism , E2F1 Transcription Factor/metabolism , Fatty Acid Synthases/metabolism , Hedgehog Proteins/metabolism , Lipogenesis/physiology , Medulloblastoma/metabolism , Neural Stem Cells/metabolism , Animals , Blotting, Western , Disease Models, Animal , Immunohistochemistry , Immunoprecipitation , Mice , Mice, Transgenic , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction/physiology
4.
Article in English | MEDLINE | ID: mdl-9827025

ABSTRACT

This work uses a new heart-perfusion technique to measure 125I-insulin binding on capillary endothelium and myofiber cell membranes in Wistar-Kyoto and spontaneously hypertensive rats. Ringer-Lock buffer was infused at a rate of 1 ml min-1 in the presence of 20 meq l-1 K+ and 125I-insulin through an aortic cannula. The effluent was collected through a catheter introduced into the right atrium. The capillary endothelial lining was removed by detergent treatment to expose the cardiac myocyte surfaces. A physical model describing a 1:1 binding stoichiometry of 125I-insulin with its receptors is proposed and the derived mathematical equations allow for the calculation of binding constants (kn), unbinding constants (k-n), dissociation constants (kd), and residency time constants (tau). The results showed that in the spontaneously hypertensive rats' hearts significant alterations were not noticed in the kinetics of insulin binding with its receptor at the capillary endothelial site compared to hearts of the normotensive control Wistar-Kyoto rats. However, at the myocyte site and in the spontaneously hypertensive rats, steric, configurational, and/or structural modifications for insulin binding with the receptor were observed as indicated by changes in insulin affinity for its receptor. Hence, alterations in insulin binding rather than reduction in insulin receptor number due to hyperinsulinemia, can be considered among the peculiarities of insulin resistance in the spontaneously hypertensive rats. Hyperinsulinemia, therefore, may be considered an upregulatory process as a consequence of insulin-resistance. The results support the hypothesis that insulin-resistance on the myocytes could be a pathophysiologic defect in insulin-receptor structure, function and affinity, and therefore myocardial function.


Subject(s)
Hypertension/metabolism , Insulin/metabolism , Myocardium/ultrastructure , Receptor, Insulin/metabolism , Animals , Cell Membrane/drug effects , Cell Membrane/ultrastructure , Cholic Acids/pharmacology , Detergents/pharmacology , Endothelium, Vascular/metabolism , Endothelium, Vascular/ultrastructure , Female , Hyperinsulinism/metabolism , Insulin/pharmacokinetics , Insulin Resistance/physiology , Iodine Radioisotopes , Mathematical Computing , Models, Biological , Myocardium/metabolism , Perfusion , Protein Binding , Rats , Rats, Inbred SHR , Rats, Inbred WKY
5.
J Pharm Sci ; 87(11): 1363-7, 1998 Nov.
Article in English | MEDLINE | ID: mdl-9811491

ABSTRACT

Peptide delivery toward its targets in an intact organ is equally as important as its routing from the systemic circulation to cell surface receptor sites. A physical model pertinent to a heart perfusion technique in Sprague-Dawley rats is presented describing reversible binding of angiotensin II and/or antagonist (DUP 753, losartan) with the microvascular endothelial receptor subtypes as well as with the cardiac myocyte receptor subtypes that are exposed to the perfusate by CHAPS-treatment. Analysis of the collected effluents are curve-fitted with a conservation equation and a first-order Bessel function. The results suggest that angiotensin II delivery and binding to the pool of receptor subtypes both at the level of the microvascular endothelium and cardiac myocyte sites differ marginally in binding affinities. The findings postulate that angiotensin II can have access to the myocyte site in an intact heart by an endothelial angiotensin II-receptor-internalization process. In addition, considering that the AT1- and AT2-receptor subtypes are present in equal proportions and have equal binding affinities with angiotensin II, the results of the 3H-DUP 753 binding indicated approximately 3-3.5 times higher affinity to the AT1-receptors subtype than angiotensin II at both the endothelial and myocyte sites. In the presence of losartan, angiotensin II binding showed higher affinity with the exposed unopposed AT2-receptor subtype than with the receptor pool, which could be due to alterations in the AT2-receptor structure and configuration. This increase in the binding affinity of angiotensin II with the AT2-receptor subtype may be categorized under the direct effect of the AT1-antagonist modality in producing cardioprotective effects.


Subject(s)
Angiotensin II/metabolism , Endothelium, Vascular/metabolism , Myocardium/metabolism , Vasoconstrictor Agents/metabolism , Animals , In Vitro Techniques , Losartan/metabolism , Male , Models, Biological , Rats , Rats, Sprague-Dawley
6.
Comp Biochem Physiol A Physiol ; 117(4): 523-30, 1997 Aug.
Article in English | MEDLINE | ID: mdl-9219356

ABSTRACT

A heart-perfusion technique was employed to measure 125I-insulin binding on capillary endothelial and myocyte cell membranes in Sprague-Dawley rats. Animals were anesthetized, and the anterior chest wall excised to expose the mediastinal contents. The right and left superior and inferior venae cavae were dissected and tied, and another tie was passed around the aorta. A polyethylene catheter was introduced into the aortic lumen from cephalad to caudad to sit with its tip above the aortic valve. Another catheter was introduced into the cavity of the right atrium and both were anchored by sutures. Oxygenated Ringer-Lock buffer containing 20 mM/L K+ and 125I-insulin was perfused at a rate of 1 mL/min via the aortic catheter. Concomitantly, the distal ascending aorta and venae cavae were ligated. The effluent was collected from the right atrial catheter at the same infusion rate. Animals were divided into two groups, the normal group and streptozotocin-induced diabetic group. Heart perfusion was done on both groups either without or after treatment with detergent (CHAPS) to remove the capillary endothelial lining. A physical model for 125I-insulin sequestration as a ligand to its receptors on endothelial and/or myocyte plasma membranes was proposed. The model described a reversible binding of ligand on cellular surface receptor concentration to fit a conservation equation and a first order Bessel function. The binding constants (kn), reversal constants (k-n), dissociation constants kd = k-n/kn, and residency time constants tau = 1/k-n of 125I-insulin in normal untreated, normal CHAPS-treated, diabetic untreated, and diabetic CHAPS-treated hearts were estimated using a theoretically generated curve-fit to the data. Since insulin receptor binding on the capillary endothelial cell surfaces may serve to transport insulin from the intravascular to the subendothelial space, and since streptozotocin-induced diabetes was shown to diminish receptor autophosphorylation and kinase activity and hence internalization of insulin, then one can conclude the following from the data. In the normal heart, removal of the capillary endothelial lining with CHAPS did not alter kn, k-n, kd, and tau of insulin binding as compared to the normal untreated, whereas in the diabetic untreated heart these constants were altered, compared to the diabetic treated. Furthermore, the kn and k-n values in the diabetic CHAPS-treated hearts were the same as for the normals untreated and CHAPS-treated, respectively. In conclusion, the dissociation constants and residency time constants of all groups indicated the possible existence of two types of insulin receptors: the capillary endothelial cell surface insulin receptors with lower residency time (low affinity receptor or combination of insulin and IGF-1 receptors) and the myocyte plasma membrane insulin receptors with higher residency times (high affinity).


Subject(s)
Diabetes Mellitus, Experimental/metabolism , Endothelium, Vascular/drug effects , Insulin/pharmacology , Iodine Radioisotopes/metabolism , Myocardium/metabolism , Receptor, Insulin/drug effects , Animals , Capillaries/drug effects , Cell Membrane/drug effects , In Vitro Techniques , Myocardium/ultrastructure , Rats , Rats, Sprague-Dawley , Streptozocin
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