Repercussion of mitochondria deformity induced by anti-Hsp90 drug 17AAG in human tumor cells
Kumar, Jonnala Ujwal
Veera Brahmendra Swamy, Cherukuvada
Sreedhar, Amere Subbarao
KAUST DepartmentBioscience Core Lab
MetadataShow full item record
AbstractInhibiting Hsp90 chaperone roles using 17AAG induces cytostasis or apoptosis in tumor cells through destabilization of several mutated cancer promoting proteins. Although mitochondria are central in deciding the fate of cells, 17AAG induced effects on tumor cell mitochondria were largely unknown. Here, we show that Hsp90 inhibition with 17AAG first affects mitochondrial integrity in different human tumor cells, neuroblastoma, cervical cancer and glial cells. Using human neuroblastoma tumor cells, we found the early effects associated with a change in mitochondrial membrane potential, elongation and engorgement of mitochondria because of an increased matrix vacuolization. These effects are specific to Hsp90 inhibition as other chemotherapeutic drugs did not induce similar mitochondrial deformity. Further, the effects are independent of oxidative damage and cytoarchitecture destabilization since cytoskeletal disruptors and mitochondrial metabolic inhibitors also do not induce similar deformity induced by 17AAG. The 1D PAGE LC MS/ MS mitochondrial proteome analysis of 17AAG treated human neuroblastoma cells showed a loss of 61% proteins from membrane, metabolic, chaperone and ribonucleoprotein families. About 31 unmapped protein IDs were identified from proteolytic processing map using Swiss-Prot accession number, and converted to the matching gene name searching the ExPASy proteomics server. Our studies display that Hsp90 inhibition effects at first embark on mitochondria of tumor cells and compromise mitochondrial integrity. the author(s), publisher and licensee Libertas Academica Ltd.
CitationA S Sreedhar, Chaturvedi Vishal, Jonnala Ujwal Kumar, Cherukuvada Veera Brahmendra Swamy, Rangaraj Nandini, et al. (2011) Repercussion of Mitochondria Deformity Induced by Anti-Hsp90 Drug 17AAG in Human Tumor Cells. DTI: 11. doi:10.4137/DTI.S6582.
PublisherLibertas Academica, Ltd.
JournalDrug Target Insights
PubMed Central IDPMC3178438
- Hsp90 inhibitors, GA and 17AAG, lead to ER stress-induced apoptosis in rat histiocytoma.
- Authors: Taiyab A, Sreedhar AS, Rao ChM
- Issue date: 2009 Jul 15
- 17AAG Treatment Accelerates Doxorubicin Induced Cellular Senescence: Hsp90 Interferes with Enforced Senescence of Tumor Cells.
- Authors: Sarangi U, Paithankar KR, Kumar JU, Subramaniam V, Sreedhar AS
- Issue date: 2012
- Blockade of Hsp90 by 17AAG antagonizes MDMX and synergizes with Nutlin to induce p53-mediated apoptosis in solid tumors.
- Authors: Vaseva AV, Yallowitz AR, Marchenko ND, Xu S, Moll UM
- Issue date: 2011 May 12
- Comparison of 17-dimethylaminoethylamino-17-demethoxy-geldanamycin (17DMAG) and 17-allylamino-17-demethoxygeldanamycin (17AAG) in vitro: effects on Hsp90 and client proteins in melanoma models.
- Authors: Smith V, Sausville EA, Camalier RF, Fiebig HH, Burger AM
- Issue date: 2005 Aug
- Pharmacological inhibition of Hsp90 as a novel antitumor strategy to target cytoarchitecture through extracellular matrix signaling.
- Authors: Chaturvedi V, Kumar JU, Paithankar KR, Vanathi P, Sreedhar AS
- Issue date: 2011 Sep