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1.
Genes Dev ; 31(20): 2067-2084, 2017 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-29138276

RESUMEN

There is limited knowledge about the metabolic reprogramming induced by cancer therapies and how this contributes to therapeutic resistance. Here we show that although inhibition of PI3K-AKT-mTOR signaling markedly decreased glycolysis and restrained tumor growth, these signaling and metabolic restrictions triggered autophagy, which supplied the metabolites required for the maintenance of mitochondrial respiration and redox homeostasis. Specifically, we found that survival of cancer cells was critically dependent on phospholipase A2 (PLA2) to mobilize lysophospholipids and free fatty acids to sustain fatty acid oxidation and oxidative phosphorylation. Consistent with this, we observed significantly increased lipid droplets, with subsequent mobilization to mitochondria. These changes were abrogated in cells deficient for the essential autophagy gene ATG5 Accordingly, inhibition of PLA2 significantly decreased lipid droplets, decreased oxidative phosphorylation, and increased apoptosis. Together, these results describe how treatment-induced autophagy provides nutrients for cancer cell survival and identifies novel cotreatment strategies to override this survival advantage.


Asunto(s)
Antineoplásicos/farmacología , Neoplasias/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Apoptosis , Autofagia , Benzamidas/farmacología , Línea Celular Tumoral , Respiración de la Célula/efectos de los fármacos , Supervivencia Celular , Compuestos Heterocíclicos con 3 Anillos/farmacología , Humanos , Gotas Lipídicas/metabolismo , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Neoplasias/enzimología , Neoplasias/patología , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Fosfolipasa A2/farmacología , Fosfolípidos/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/metabolismo , Pirimidinas/farmacología , Células Tumorales Cultivadas
2.
Anal Chem ; 90(20): 11756-11759, 2018 10 16.
Artículo en Inglés | MEDLINE | ID: mdl-30269481

RESUMEN

Proteome profiling of circulating tumor cells (CTCs) can provide crucial insight into disease progression and the role of CTCs in tumor metastasis. We describe an integrated workflow to measure global protein expression in 1-5 spiked CTCs enriched from whole blood by immunodensity gradient centrifugation. Enriched CTCs were purified and collected by laser capture microdissection, prepared using a recently developed nanodroplet-based processing platform (nanoPOTS), and finally analyzed by ultrasensitive nanoLC-MS/MS. The workflow was capable of identifying an average of 164 and 607 protein groups from samples comprising 1 and 5 LNCaP cells, respectively, that were isolated from human whole blood. A panel of prostate cancer-specific proteins were identified and quantified, which was used to differentiate between spiked CTCs and white blood cells.


Asunto(s)
Captura por Microdisección con Láser , Nanopartículas/química , Nanotecnología , Proteínas de Neoplasias/sangre , Células Neoplásicas Circulantes/química , Proteoma/análisis , Línea Celular Tumoral , Centrifugación , Cromatografía Liquida , Humanos , Inmunohistoquímica , Células Neoplásicas Circulantes/metabolismo , Tamaño de la Partícula , Espectrometría de Masas en Tándem
4.
Cell Rep Med ; 2(5): 100267, 2021 05 18.
Artículo en Inglés | MEDLINE | ID: mdl-34095877

RESUMEN

The lack of effective treatment options for advanced non-clear cell renal cell carcinoma (NCCRCC) is a critical unmet clinical need. Applying a high-throughput drug screen to multiple human kidney cancer cells, we identify the combination of the VEGFR-MET inhibitor cabozantinib and the SRC inhibitor dasatinib acts synergistically in cells to markedly reduce cell viability. Importantly, the combination is well tolerated and causes tumor regression in vivo. Transcriptional and phosphoproteomic profiling reveals that the combination converges to downregulate the MAPK-ERK signaling pathway, a result not predicted by single-agent analysis alone. Correspondingly, the addition of a MEK inhibitor synergizes with either dasatinib or cabozantinib to increase its efficacy. This study, by using approved, clinically relevant drugs, provides the rationale for the design of effective combination treatments in NCCRCC that can be rapidly translated to the clinic.


Asunto(s)
Anilidas/farmacología , Carcinoma de Células Renales/tratamiento farmacológico , Dasatinib/farmacología , Piridinas/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Línea Celular Tumoral , Humanos , Neoplasias Renales/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/administración & dosificación , Transducción de Señal/efectos de los fármacos , Familia-src Quinasas/metabolismo
5.
Metabolites ; 9(5)2019 Apr 26.
Artículo en Inglés | MEDLINE | ID: mdl-31035489

RESUMEN

As the most common cancer in men, prostate cancer is molecularly heterogeneous. Contributing to this heterogeneity are the poorly understood metabolic adaptations of the two main types of prostate cancer, i.e., adenocarcinoma and small cell neuroendocrine carcinoma (SCNC), the latter being more aggressive and lethal. Using transcriptomics, untargeted metabolomics and lipidomics profiling on LASCPC-01 (prostate SCNC) and LNCAP (prostate adenocarcinoma) cell lines, we found significant differences in the cellular phenotypes of the two cell lines. Gene set enrichment analysis on the transcriptomics data showed 62 gene sets were upregulated in LASCPC-01, while 112 gene sets were upregulated in LNCAP. ChemRICH analysis on metabolomics and lipidomics data revealed a total of 25 metabolite clusters were significantly different. LASCPC-01 exhibited a higher glycolytic activity and lower levels of triglycerides, while the LNCAP cell line showed increases in one-carbon metabolism as an exit route of glycolytic intermediates and a decrease in carnitine, a mitochondrial lipid transporter. Our findings pinpoint differences in prostate neuroendocrine carcinoma versus prostate adenocarcinoma that could lead to new therapeutic targets in each type.

6.
Oncotarget ; 8(42): 71447-71455, 2017 Sep 22.
Artículo en Inglés | MEDLINE | ID: mdl-29069718

RESUMEN

Increased AR activity has been shown to be preserved in spatially distinct metastatic tumors from the same patient suggesting the requirement for lineage-specific dependencies for metastatic castration resistant prostate cancer (mCRPC). Amplification of the AR gene is a common mechanism by which mCRPC increase AR activity. To determine whether AR amplification in circulating tumor cells (CTC) could complement metastatic tissue biopsies in men undergoing treatment for mCRPC, we developed a novel two-step assay to isolate CTCs and subsequently analyzed AR amplification status in CTCs and matched biopsy tissue from the same patient by fluorescence in situ hybridization (FISH). AR gene status in CTCs showed strong concordance with AR gene status in matched tissue samples in 24 of 25 patients (Correlation: 96%; Kappa: 0.83; Sensitivity: 100%, Specificity: 83%). Our work demonstrates that AR amplification is conserved between CTCs and biopsies and that CTCs can serve as non-invasive surrogate to document AR amplification in mCRPC.

7.
Oncotarget ; 6(42): 44675-87, 2015 Dec 29.
Artículo en Inglés | MEDLINE | ID: mdl-26625308

RESUMEN

The intracytoplasmic tyrosine kinase Src serves both as a conduit and a regulator for multiple processes required for the proliferation and survival cancer cells. In some cancers, Src engages with receptor tyrosine kinases to mediate downstream signaling and in other cancers, it regulates gene expression. Src therefore represents a viable oncologic target. However, clinical responses to Src inhibitors, such as dasatinib have been disappointing to date. We identified Stat3 signaling as a potential bypass mechanism that enables renal cell carcinoma (RCC) cells to escape dasatinib treatment. Combined Src-Stat3 inhibition using dasatinib and CYT387 (a JAK/STAT inhibitor) synergistically reduced cell proliferation and increased apoptosis in RCC cells. Moreover, dasatinib and CYT387 combine to suppress YAP1, a transcriptional co-activator that promotes cell proliferation, survival and organ size. Importantly, this combination was well tolerated, and caused marked tumor inhibition in RCC xenografts. These results suggest that combination therapy with inhibitors of Stat3 signaling may be a useful therapeutic approach to increase the efficacy of Src inhibitors.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Benzamidas/farmacología , Carcinoma de Células Renales/tratamiento farmacológico , Dasatinib/farmacología , Neoplasias Renales/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Factor de Transcripción STAT3/antagonistas & inhibidores , Familia-src Quinasas/antagonistas & inhibidores , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Apoptosis/efectos de los fármacos , Carcinoma de Células Renales/enzimología , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Regulación Neoplásica de la Expresión Génica , Neoplasias Renales/enzimología , Neoplasias Renales/genética , Neoplasias Renales/patología , Ratones , Terapia Molecular Dirigida , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacos , Factores de Tiempo , Factores de Transcripción , Transcripción Genética , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Proteínas Señalizadoras YAP , Familia-src Quinasas/metabolismo
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