RESUMO
Building molecular correlates of drug resistance in cancer and exploiting them for therapeutic intervention remains a pressing clinical need. To identify factors that impact drug resistance herein we built a model that couples inherent cell-based response toward drugs with transcriptomes of resistant/sensitive cells. To test this model, we focused on a group of genes called metastasis suppressor genes (MSGs) that influence aggressiveness and metastatic potential of cancers. Interestingly, modeling of 84 000 drug response transcriptome combinations predicted multiple MSGs to be associated with resistance of different cell types and drugs. As a case study, on inducing MSG levels in a drug resistant breast cancer line resistance to anticancer drugs caerulomycin, camptothecin and topotecan decreased by more than 50-60%, in both culture conditions and also in tumors generated in mice, in contrast to control un-induced cells. To our knowledge, this is the first demonstration of engineered reversal of drug resistance in cancer cells based on a model that exploits inherent cellular response profiles.
Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Genes Supressores de Tumor , Neoplasias/genética , Engenharia Celular , Linhagem Celular Tumoral , Células Epiteliais/metabolismo , Perfilação da Expressão Gênica , Humanos , Mesoderma/metabolismo , Metástase Neoplásica , Neoplasias/metabolismoRESUMO
Heat Shock Protein 90 (HSP90) is a potential drug target for cancer therapy as it is often dysregulated in several cancers, including lung, breast, pancreatic, and prostate cancers. In cancer, HSP90 fails to maintain the structural and functional integrity of its several client proteins which are involved in the hallmarks of cancer such as cell proliferation, invasion, migration, angiogenesis, and apoptosis. Several small molecule inhibitors of HSP90 have been shown to exhibit anticancer effects in vitro and in vivo animal models. However, a few of them are currently under clinical studies. The status and potential limitations of these inhibitors are discussed here. Studies demonstrate that several noncoding RNAs (ncRNAs) such as microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) regulate HSP90 and its client proteins to modulate cellular processes to exhibit oncogenic or tumor suppressing properties. Over the last decade, miRNAs and lncRNAs have drawn significant interest from the scientific community as therapeutic agents or targets for clinical applications. Here, we discuss the detailed mechanistic regulation of HSP90 and its client proteins by ncRNAs. Moreover, we highlight the significance of these ncRNAs as potential therapeutic agents/targets, and the challenges associated with ncRNA-based therapies. This article aims to provide a holistic view on HSP90-regulating ncRNAs for the development of novel therapeutic strategies to combat cancer.
Assuntos
MicroRNAs , Neoplasias da Próstata , RNA Longo não Codificante , Masculino , Animais , Humanos , RNA Longo não Codificante/genética , RNA não Traduzido/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas de Choque Térmico HSP90/genética , Proteínas de Choque Térmico HSP90/metabolismoAssuntos
Antituberculosos/farmacologia , Apoptose/efeitos dos fármacos , MicroRNAs/antagonistas & inibidores , Estreptomicina/farmacologia , Antituberculosos/química , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Linhagem Celular Tumoral , Humanos , MicroRNAs/metabolismo , Neoplasias/tratamento farmacológico , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Estreptomicina/química , Raios UltravioletaRESUMO
Chaperone protein Hsp90 maintains functional integrity and maturation of a large number of cellular proteins including transcription factors, kinases, etc. It is often over-expressed in cancer cells for simultaneous maintenance of many non-regulated and/or genetically mutated proteins. Small molecule-based regimens inhibiting over-expressing Hsp90 in cancer cells often plagued with improper targeting leading to non-specific toxicity. Recently using a glucocorticoid receptor (GR)-targeted cationic lipoplex, we observed cancer cell-specific GR-transactivation and transgene expression by utilizing an unprecedentedly compromised chaperone-activity of cancer cell-associated Hsp90. In normal cells, GR is expressed ubiquitously and is highly regulated and chaperoned by Hsp90. This does not allow cancer cell-alike GR-mediated transgene expression. As a novel anticancer strategy, we showed that compromising Hsp90 in cancer cells can be utilized to selectively deplete its own level by delivering a specially designed artificial miRNA-plasmid against Hsp90 (amiR-Hsp90). Practically, GR-mediated delivery of amiR-Hsp90 plasmid in tumor-bearing mice, depleted Hsp90, critically down-regulated levels of Akt, VEGFR2 and other Hsp90-client proteins but up-regulated wild-type p53 in tumor. These enforced apoptosis in angiogenic vessels and in tumor mass and significantly shrunk tumor-volume. The present study describes gene therapy strategy against Hsp90 using a new GR-targeted liposome-amiR-Hsp90 lipoplex formulation for treating cancer.