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PMID: 18598947 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

A molecule targeting VHL-deficient renal cell carcinoma that induces autophagy.

Cancer cell ·Vol. 14 ·No. 1 ·2008-07-08 ·Pages 90-102

Turcotte S, Chan DA, Sutphin PD, Hay MP, Denny WA, Giaccia AJ

Abstract

Renal cell carcinomas (RCCs) are refractory to standard therapies. The von Hippel-Lindau (VHL) tumor suppressor gene is inactivated in 75% of RCCs. By screening for small molecules selectively targeting VHL-deficient RCC cells, we identified STF-62247. STF-62247 induces cytotoxicity and reduces tumor growth of VHL-deficient RCC cells compared to genetically matched cells with wild-type VHL. STF-62247-stimulated toxicity occurs in a HIF-independent manner through autophagy. Reduction of protein levels of essential autophagy pathway components reduces sensitivity of VHL-deficient cells to STF-62247. Using a yeast deletion pool, we show that loss of proteins involved in Golgi trafficking increases killing by STF-62247. Thus, we have found a small molecule that selectively induces cell death in VHL-deficient cells, representing a paradigm shift for targeted therapy.

MeSH Terms
Animals Antineoplastic Agents/chemistry,pharmacology Autophagy/drug effects Autophagy-Related Protein 5 Basic Helix-Loop-Helix Transcription Factors/metabolism Carcinoma, Renal Cell/enzymology,genetics,metabolism,pathology Cell Line, Tumor Cell Proliferation/drug effects Cell Survival/drug effects Dose-Response Relationship, Drug Gene Expression Regulation, Neoplastic Gene Silencing Golgi Apparatus/metabolism Humans Hydrogen-Ion Concentration Hypoxia-Inducible Factor 1/metabolism Inhibitory Concentration 50 Kidney Neoplasms/enzymology,genetics,metabolism,pathology Male Mice Mice, SCID Microtubule-Associated Proteins/metabolism Molecular Structure Phosphatidylinositol 3-Kinases/metabolism Protein Transport Pyridines/pharmacology Structure-Activity Relationship Thiazoles/pharmacology Time Factors Transfection Vacuoles/drug effects,metabolism,pathology Von Hippel-Lindau Tumor Suppressor Protein/genetics,metabolism Yeasts/drug effects,growth & development,metabolism
Chemicals
Antineoplastic Agents Atg5 protein, mouse Autophagy-Related Protein 5 Basic Helix-Loop-Helix Transcription Factors Hypoxia-Inducible Factor 1 Microtubule-Associated Proteins Pyridines STF 62247 Thiazoles endothelial PAS domain-containing protein 1 Von Hippel-Lindau Tumor Suppressor Protein Phosphatidylinositol 3-Kinases
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Turcotte Sandra
Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Chan Denise A
Sutphin Patrick D
Hay Michael P
Denny William A
Giaccia Amato J
References (66)
66 references, click to expand
  1. Opportunities and obstacles to combination targeted therapy in renal cell cancer.
    Clin Cancer Res. 2007 Jan 15;13(2 Pt 2):764s-769s PMID: 17255307
  2. ESCRT-III dysfunction causes autophagosome accumulation and neurodegeneration.
    Curr Biol. 2007 Sep 18;17(18):1561-7 PMID: 17683935
  3. The von Hippel-Lindau tumor suppressor protein mediates ubiquitination of activated atypical protein kinase C.
    J Biol Chem. 2001 Nov 23;276(47):43611-7 PMID: 11574546
  4. Disruption of autophagy at the maturation step by the carcinogen lindane is associated with the sustained mitogen-activated protein kinase/extracellular signal-regulated kinase activity.
    Cancer Res. 2006 Jul 1;66(13):6861-70 PMID: 16818664
  5. p73 regulates DRAM-independent autophagy that does not contribute to programmed cell death.
    Cell Death Differ. 2007 Jun;14(6):1071-9 PMID: 17304243
  6. Dissection of autophagosome formation using Apg5-deficient mouse embryonic stem cells.
    J Cell Biol. 2001 Feb 19;152(4):657-68 PMID: 11266458
  7. Isolation of the ALG5 locus encoding the UDP-glucose:dolichyl-phosphate glucosyltransferase from Saccharomyces cerevisiae.
    Eur J Biochem. 1994 Aug 15;224(1):71-9 PMID: 8076653
  8. The anticancer drug imatinib induces cellular autophagy.
    Leukemia. 2007 May;21(5):936-42 PMID: 17330103
  9. Role of LAMP-2 in lysosome biogenesis and autophagy.
    Mol Biol Cell. 2002 Sep;13(9):3355-68 PMID: 12221139
  10. Starvation and ULK1-dependent cycling of mammalian Atg9 between the TGN and endosomes.
    J Cell Sci. 2006 Sep 15;119(Pt 18):3888-900 PMID: 16940348
  11. Inhibition of HIF2alpha is sufficient to suppress pVHL-defective tumor growth.
    PLoS Biol. 2003 Dec;1(3):E83 PMID: 14691554
  12. The role of autophagy in cancer development and response to therapy.
    Nat Rev Cancer. 2005 Sep;5(9):726-34 PMID: 16148885
  13. Resveratrol-induced autophagocytosis in ovarian cancer cells.
    Cancer Res. 2004 Jan 15;64(2):696-703 PMID: 14744787
  14. Endoplasmic reticulum stress triggers autophagy.
    J Biol Chem. 2006 Oct 6;281(40):30299-304 PMID: 16901900
  15. Human CHMP6, a myristoylated ESCRT-III protein, interacts directly with an ESCRT-II component EAP20 and regulates endosomal cargo sorting.
    Biochem J. 2005 Apr 1;387(Pt 1):17-26 PMID: 15511219
  16. VHL expression in renal cell carcinoma sensitizes to bortezomib (PS-341) through an NF-kappaB-dependent mechanism.
    Oncogene. 2005 Feb 24;24(9):1563-70 PMID: 15608669
  17. HIF-1 as a target for drug development.
    Nat Rev Drug Discov. 2003 Oct;2(10):803-11 PMID: 14526383
  18. Autophagy as a regulated pathway of cellular degradation.
    Science. 2000 Dec 1;290(5497):1717-21 PMID: 11099404
  19. Transforming growth factor alpha is a target for the von Hippel-Lindau tumor suppressor.
    Cancer Res. 1998 Jan 15;58(2):226-31 PMID: 9443397
  20. Role of prolyl hydroxylation in oncogenically stabilized hypoxia-inducible factor-1alpha.
    J Biol Chem. 2002 Oct 18;277(42):40112-7 PMID: 12186875
  21. Pleiotropic effects of HIF-1 blockade on tumor radiosensitivity.
    Cancer Cell. 2005 Aug;8(2):99-110 PMID: 16098463
  22. Autophagy suppresses tumor progression by limiting chromosomal instability.
    Genes Dev. 2007 Jun 1;21(11):1367-81 PMID: 17510285
  23. Rab7 is required for the normal progression of the autophagic pathway in mammalian cells.
    J Cell Sci. 2004 Jun 1;117(Pt 13):2687-97 PMID: 15138286
  24. Renal-cell carcinoma.
    N Engl J Med. 1996 Sep 19;335(12):865-75 PMID: 8778606
  25. Negative regulation of hypoxia-inducible genes by the von Hippel-Lindau protein.
    Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):10595-9 PMID: 8855223
  26. HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing.
    Science. 2001 Apr 20;292(5516):464-8 PMID: 11292862
  27. Induction of macroautophagy in human colon cancer cells by soybean B-group triterpenoid saponins.
    Carcinogenesis. 2005 Jan;26(1):159-67 PMID: 15471899
  28. Targeting von Hippel-Lindau pathway in renal cell carcinoma.
    Clin Cancer Res. 2006 Dec 15;12(24):7215-20 PMID: 17189392
  29. Chemokine receptor CXCR4 downregulated by von Hippel-Lindau tumour suppressor pVHL.
    Nature. 2003 Sep 18;425(6955):307-11 PMID: 13679920
  30. Inhibition of hypoxia-inducible factor is sufficient for growth suppression of VHL-/- tumors.
    Mol Cancer Res. 2004 Feb;2(2):89-95 PMID: 14985465
  31. Dead cells don't form tumors: HIF-dependent cytotoxins.
    Cell Cycle. 2004 Feb;3(2):160-3 PMID: 14712081
  32. Principles for the buffering of genetic variation.
    Science. 2001 Feb 9;291(5506):1001-4 PMID: 11232561
  33. Active cell death induced by the anti-estrogens tamoxifen and ICI 164 384 in human mammary carcinoma cells (MCF-7) in culture: the role of autophagy.
    Carcinogenesis. 1996 Aug;17(8):1595-607 PMID: 8761415
  34. Uridine diphosphate-glucose transport into the endoplasmic reticulum of Saccharomyces cerevisiae: in vivo and in vitro evidence.
    Mol Biol Cell. 1999 Apr;10(4):1019-30 PMID: 10198054
  35. Using small molecules to overcome drug resistance induced by a viral oncogene.
    Cancer Cell. 2006 Feb;9(2):133-46 PMID: 16473280
  36. Regulation of microtubule stability by the von Hippel-Lindau tumour suppressor protein pVHL.
    Nat Cell Biol. 2003 Jan;5(1):64-70 PMID: 12510195
  37. Post-transcriptional regulation of vascular endothelial growth factor mRNA by the product of the VHL tumor suppressor gene.
    Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):10589-94 PMID: 8855222
  38. Cloning and genomic organization of beclin 1, a candidate tumor suppressor gene on chromosome 17q21.
    Genomics. 1999 Jul 1;59(1):59-65 PMID: 10395800
  39. Induction of autophagic cell death in malignant glioma cells by arsenic trioxide.
    Cancer Res. 2003 May 1;63(9):2103-8 PMID: 12727826
  40. Beclin-phosphatidylinositol 3-kinase complex functions at the trans-Golgi network.
    EMBO Rep. 2001 Apr;2(4):330-5 PMID: 11306555
  41. Human Apg3p/Aut1p homologue is an authentic E2 enzyme for multiple substrates, GATE-16, GABARAP, and MAP-LC3, and facilitates the conjugation of hApg12p to hApg5p.
    J Biol Chem. 2002 Apr 19;277(16):13739-44 PMID: 11825910
  42. Radiation-induced autophagy is associated with LC3 and its inhibition sensitizes malignant glioma cells.
    Int J Oncol. 2005 May;26(5):1401-10 PMID: 15809734
  43. Hypoxia-inducible expression of a natural cis-antisense transcript inhibits endothelial nitric-oxide synthase.
    J Biol Chem. 2007 May 25;282(21):15652-66 PMID: 17403686
  44. Lysyl oxidase is essential for hypoxia-induced metastasis.
    Nature. 2006 Apr 27;440(7088):1222-6 PMID: 16642001
  45. Hsp90 regulates a von Hippel Lindau-independent hypoxia-inducible factor-1 alpha-degradative pathway.
    J Biol Chem. 2002 Aug 16;277(33):29936-44 PMID: 12052835
  46. Oxysterol-binding protein and vesicle-associated membrane protein-associated protein are required for sterol-dependent activation of the ceramide transport protein.
    Mol Biol Cell. 2006 Jun;17(6):2604-16 PMID: 16571669
  47. Autophagy and cell death.
    Curr Top Dev Biol. 2007;78:217-45 PMID: 17338918
  48. The concept of synthetic lethality in the context of anticancer therapy.
    Nat Rev Cancer. 2005 Sep;5(9):689-98 PMID: 16110319
  49. The von Hippel-Lindau tumor suppressor protein sensitizes renal cell carcinoma cells to tumor necrosis factor-induced cytotoxicity by suppressing the nuclear factor-kappaB-dependent antiapoptotic pathway.
    Cancer Res. 2003 Nov 1;63(21):7076-80 PMID: 14612498
  50. Synergistic augmentation of rapamycin-induced autophagy in malignant glioma cells by phosphatidylinositol 3-kinase/protein kinase B inhibitors.
    Cancer Res. 2005 Apr 15;65(8):3336-46 PMID: 15833867
  51. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation.
    Science. 2001 Apr 20;292(5516):468-72 PMID: 11292861
  52. Tumour suppression by the human von Hippel-Lindau gene product.
    Nat Med. 1995 Aug;1(8):822-6 PMID: 7585187
  53. 2ME2 inhibits tumor growth and angiogenesis by disrupting microtubules and dysregulating HIF.
    Cancer Cell. 2003 Apr;3(4):363-75 PMID: 12726862
  54. Autophagy-related pathways and specific role of sterol glucoside in yeasts.
    Autophagy. 2007 May-Jun;3(3):263-5 PMID: 17329963
  55. Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer.
    Nat Med. 2006 Jan;12(1):122-7 PMID: 16341243
  56. Microtubules facilitate autophagosome formation and fusion of autophagosomes with endosomes.
    Traffic. 2006 Feb;7(2):129-45 PMID: 16420522
  57. The von Hippel-Lindau tumor suppressor protein is required for proper assembly of an extracellular fibronectin matrix.
    Mol Cell. 1998 Jun;1(7):959-68 PMID: 9651579
  58. DRAM, a p53-induced modulator of autophagy, is critical for apoptosis.
    Cell. 2006 Jul 14;126(1):121-34 PMID: 16839881
  59. LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing.
    EMBO J. 2000 Nov 1;19(21):5720-8 PMID: 11060023
  60. Identification of small molecule inhibitors of hypoxia-inducible factor 1 transcriptional activation pathway.
    Cancer Res. 2002 Aug 1;62(15):4316-24 PMID: 12154035
  61. Metabolic catastrophe as a means to cancer cell death.
    J Cell Sci. 2007 Feb 1;120(Pt 3):379-83 PMID: 17251378
  62. Autophagy is activated for cell survival after endoplasmic reticulum stress.
    Mol Cell Biol. 2006 Dec;26(24):9220-31 PMID: 17030611
  63. The evolutionarily conserved domain of Beclin 1 is required for Vps34 binding, autophagy and tumor suppressor function.
    Autophagy. 2005 Apr;1(1):46-52 PMID: 16874027
  64. Constitutive activation of nuclear factor-kappaB prevents TRAIL-induced apoptosis in renal cancer cells.
    Oncogene. 2001 Jun 28;20(29):3888-96 PMID: 11439352
  65. Tumor suppression by the von Hippel-Lindau protein requires phosphorylation of the acidic domain.
    J Biol Chem. 2005 Jun 10;280(23):22205-11 PMID: 15824109
  66. Identification of the RNA polymerase II subunit hsRPB7 as a novel target of the von Hippel-Lindau protein.
    EMBO J. 2003 Aug 15;22(16):4249-59 PMID: 12912922
Article Info
Journal
Cancer cell
Abbr.
Cancer Cell
ISSN
1878-3686
DOI
10.1016/j.ccr.2008.06.004
Published
2008-07-08
Pages
90-102
Language
English
Region
United States
NLM ID
101130617
PMCID
PMC2819422
Subset
IM
Grants
NCI NIH HHS · NCI-CA-123823 · United States
NCI NIH HHS · P01 CA082566 · United States
NCI NIH HHS · P01 CA082566-070004 · United States
NCI NIH HHS · NCI-CA-082566 · United States
NCI NIH HHS · F32 CA123823 · United States
External Links
PubMed source DOI: 10.1016/j.ccr.2008.06.004 PMC Full Text View journal details
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