| [PMID]: | 21199801 |
| [Au] Autor: | Woldemichael GM; Turbyville TJ; Linehan WM; McMahon JB |
| [Ad] Endereço: | Molecular Targets Laboratory, SAIC-Frederick, Inc., National Cancer Institute, Frederick, Maryland 21702, USA. woldemichaelg@mail.nih.gov |
| [Ti] Título: | Carminomycin I is an apoptosis inducer that targets the Golgi complex in clear cell renal carcinoma cells. |
| [So] Source: | Cancer Res;71(1):134-42, 2011 Jan 01. |
| [Is] ISSN: | 1538-7445 |
| [Cp] País de publicação: | United States |
| [La] Idioma: | eng |
| [Ab] Resumo: | Clear cell renal cell carcinoma (CCRCC) evolves due to mutations in the Von Hippel-Lindau (VHL) tumor suppressor gene. Although the loss of VHL enables survival and proliferation of CCRCC cells, it is also expected to introduce vulnerabilities that may be exploited for therapeutics discovery. To this end, we developed a high-throughput screen to identify small molecules derived from plants, microorganisms, and marine organisms to which CCRCC cells are sensitive. Screening over 8,000 compounds using this approach, we report here the identification of the microbially derived compound carminomycin I (CA) as an effective inhibitor of VHL-defective (VHL(-/-)) CCRCC cell proliferation. CA also induced apoptosis in CCRCC cells by a mechanism independent of p53 or hypoxia-inducible factor 2. We found that P-glycoprotein (P-gp) sequestered CA within the Golgi complex. Interestingly, Golgi sequestration was critical for the antiproliferative effects of CA and P-gp inhibitors abrogated this activity. Furthermore, CA induced cleavage of the Golgi protein p115 and the translocation of its C-terminal fragment to the nucleus. Finally, examination of the activity of the VHL-interacting Golgi protein, endoplasmic reticulum-Golgi intermediate compartment, ERGIC-53 showed that VHL could mediate protection from CA in CCRCC cells. Our natural product-based screening approach has revealed the P-gp-mediated localization of anticancer compounds within the Golgi in CCRCC cells as a potential strategy of targeting VHL-deficient CCRCC cells. |
| [Mh] Termos MeSH primário: |
Antibióticos Antineoplásicos/farmacologia
Apoptose/efeitos dos fármacos
Carcinoma de Células Renais/patologia
Carrubicina/farmacologia
Complexo de Golgi/efeitos dos fármacos
Neoplasias Renais/patologia
|
| [Mh] Termos MeSH secundário: |
Sequência de Bases
Western Blotting
Linhagem Celular Tumoral
Ensaio de Imunoadsorção Enzimática
Seres Humanos
Imuno-Histoquímica
Interferência de RNA
Reação em Cadeia da Polimerase Via Transcriptase Reversa
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| [Pt] Tipo de publicação: | JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, N.I.H., INTRAMURAL |
[Nm] Nome de substância:
| 0 (Antibiotics, Antineoplastic); E7437K3983 (Carubicin) |
| [Em] Mês de entrada: | 1102 |
| [Cu] Atualização por classe: | 170220 |
[Lr] Data última revisão:
| 170220 |
| [Sb] Subgrupo de revista: | IM |
| [Da] Data de entrada para processamento: | 110105 |
| [St] Status: | MEDLINE |
| [do] DOI: | 10.1158/0008-5472.CAN-10-0757 |
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