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1.
Vaccines (Basel) ; 3(3): 519-43, 2015 Jul 06.
Article in English | MEDLINE | ID: mdl-26350593

ABSTRACT

Despite the promise of targeted therapies, there remains an urgent need for effective treatment for esophageal cancer (EC) and triple-negative breast cancer (TNBC). Current FDA-approved drugs have significant problems of toxicity, safety, selectivity, efficacy and development of resistance. In this manuscript, we demonstrate that rationally designed peptide vaccines/mimics are a viable therapeutic strategy for blocking aberrant molecular signaling pathways with high affinity, specificity, potency and safety. Specifically, we postulate that novel combination treatments targeting members of the EGFR family and IGF-1R will yield significant anti-tumor effects in in vitro models of EC and TNBC possibly overcoming mechanisms of resistance. We show that the combination of HER-1 and HER-2 or HER-1 and IGF-1R peptide mimics/vaccine antibodies exhibited enhanced antitumor properties with significant inhibition of tumorigenesis in OE19 EC and MDA-MB-231 TNBC cell lines. Our work elucidates the mechanisms of HER-1/IGF-1R and HER-1/HER-2 signaling in these cancer cell lines, and the promising results support the rationale for dual targeting with HER-1 and HER-2 or IGF-1R as an improved treatment regimen for advanced therapy tailored to difference types of cancer.

2.
PLoS Pathog ; 11(2): e1004639, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25646845

ABSTRACT

The Plasmodium falciparum cGMP-dependent protein kinase (PfPKG) is a key regulator across the malaria parasite life cycle. Little is known about PfPKG's activation mechanism. Here we report that the carboxyl cyclic nucleotide binding domain functions as a "gatekeeper" for activation by providing the highest cGMP affinity and selectivity. To understand the mechanism, we have solved its crystal structures with and without cGMP at 2.0 and 1.9 Å, respectively. These structures revealed a PfPKG-specific capping triad that forms upon cGMP binding, and disrupting the triad reduces kinase activity by 90%. Furthermore, mutating these residues in the parasite prevents blood stage merozoite egress, confirming the essential nature of the triad in the parasite. We propose a mechanism of activation where cGMP binding allosterically triggers the conformational change at the αC-helix, which bridges the regulatory and catalytic domains, causing the capping triad to form and stabilize the active conformation.


Subject(s)
Cyclic GMP-Dependent Protein Kinases/metabolism , Life Cycle Stages/physiology , Merozoites/physiology , Plasmodium falciparum/physiology , Protozoan Proteins/metabolism , Amino Acid Sequence , Crystallography, X-Ray , Immunoblotting , Molecular Sequence Data , Polymerase Chain Reaction , Protein Conformation , Transfection
3.
Mol Pharmacol ; 87(2): 150-61, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25391374

ABSTRACT

Resistance to the human epidermal growth factor receptor (HER2)-targeted antibody trastuzumab is a major clinical concern in the treatment of HER2-positive metastatic breast cancer. Increased expression or signaling from the insulin-like growth factor-1 receptor (IGF-1R) has been reported to be associated with trastuzumab resistance. However, the specific molecular and biologic mechanisms through which IGF-1R promotes resistance or disease progression remain poorly defined. In this study, we found that the major biologic effect promoted by IGF-1R was invasion, which was mediated by both Src-focal adhesion kinase (FAK) signaling and Forkhead box protein M1 (FoxM1). Cotargeting IGF-1R and HER2 using either IGF-1R antibodies or IGF-1R short hairpin RNA in combination with trastuzumab resulted in significant but modest growth inhibition. Reduced invasion was the most significant biologic effect achieved by cotargeting IGF-1R and HER2 in trastuzumab-resistant cells. Constitutively active Src blocked the anti-invasive effect of IGF-1R/HER2 cotargeted therapy. Furthermore, knockdown of FoxM1 blocked IGF-1-mediated invasion, and dual targeting of IGF-1R and HER2 reduced expression of FoxM1. Re-expression of FoxM1 restored the invasive potential of IGF-1R knockdown cells treated with trastuzumab. Overall, our results strongly indicate that therapeutic combinations that cotarget IGF-1R and HER2 may reduce the invasive potential of cancer cells that are resistant to trastuzumab through mechanisms that depend in part on Src and FoxM1.


Subject(s)
Breast Neoplasms/metabolism , Focal Adhesion Kinase 1/biosynthesis , Forkhead Transcription Factors/biosynthesis , Gene Expression Regulation, Neoplastic , Receptor, ErbB-2/biosynthesis , Receptor, IGF Type 1/biosynthesis , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Cell Line, Tumor , Female , Forkhead Box Protein M1 , Genes, src/physiology , Humans , RNA, Small Interfering/administration & dosage , RNA, Small Interfering/genetics , Receptor, ErbB-2/antagonists & inhibitors , Receptor, ErbB-2/genetics , Receptor, IGF Type 1/antagonists & inhibitors , Receptor, IGF Type 1/genetics , Signal Transduction/physiology
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