Repercussion of Mitochondria Deformity Induced by Anti-Hsp90 Drug 17AAG in Human Tumor Cells.

Citation data:

Drug target insights, ISSN: 1177-3928, Vol: 5, Issue: 5, Page: 11-32

Publication Year:
2011
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Citations 5
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Repository URL:
http://hdl.handle.net/10754/325367
PMID:
22087060
DOI:
10.4137/dti.s6582
PMCID:
PMC3178438; 3178438
Author(s):
Vishal, Chaturvedi; Kumar, Jonnala Ujwal; Veera Brahmendra Swamy, Cherukuvada; Nandini, Rangaraj; Srinivas, Gunda; Kumaresan, Rathinam; Shashi, Singh; Sreedhar, Amere Subbarao
Publisher(s):
SAGE Publications; Libertas Academica; Libertas Academica, Ltd.
Tags:
Pharmacology, Toxicology and Pharmaceutics; Biochemistry, Genetics and Molecular Biology; Medicine; ??m; 17AAG; Hsp90; Mitochondria; Tumor cells; cisplatin; curcumin; cytochalasin D; cytochrome c; digitonin; heat shock protein 90; hydrogen peroxide; novobiocin; paclitaxel; radicicol; reactive oxygen metabolite; tanespimycin; vincristine; cell vacuole; controlled study; glioblastoma; human cell; liquid chromatography; liver mitochondrion; mass spectrometry; mitochondrial deformity; mitochondrial elongation; mitochondrial membrane potential; mitochondrion; mitochondrion swelling; neuroblastoma cell; polyacrylamide gel electrophoresis; proteomics; tumor cell; uterine cervix cancer
article description
Inhibiting 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.