Document Detail


Human TSC-associated renal angiomyolipoma cells are hypersensitive to ER stress.
MedLine Citation:
PMID:  22791333     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Tuberous sclerosis complex (TSC), an inherited tumor predisposition syndrome associated with mutations in TSC1 or TSC2, affects ∼1 in 6,000 individuals. Eighty percent of TSC patients develop renal angiomyolipomas, and renal involvement is a major contributor to patient morbidity and mortality. Recent work has shown that mammalian target of rapamycin complex 1 (mTORC1) inhibition caused angiomyolipoma shrinkage but that this treatment may cause cytostatic not a cytotoxic effect. Endoplasmic reticulum (ER) stress can develop in TSC-associated cells due to mTORC1-driven protein translation. We hypothesized that renal angiomyolipoma cells experience ER stress that can be leveraged to result in targeted cytotoxicity. We used immortalized human angiomyolipoma cells stably transfected with empty vector or TSC2 (encoding tuberin). Using cell number quantification and cell death assays, we found that mTORC1 inhibition with RAD001 suppressed angiomyolipoma cell proliferation in a cytostatic manner. Angiomyolipoma cells exhibited enhanced sensitivity to proteasome inhibitor-induced ER stress compared with TSC2-rescued cells. After proteasome inhibition with MG-132, Western blot analyses showed greater induction of C/EBP-homologous protein (CHOP) and more poly (ADP-ribose) polymerase (PARP) and caspase-3 cleavage, supporting ER stress-induced apoptosis. Live cell numbers also were decreased and cell death increased by MG-132 in angiomyolipoma cells compared with TSC2 rescued. Intriguingly, while pretreatment of angiomyolipoma cells with RAD001 attenuated CHOP and BiP induction, apoptotic markers cleaved PARP and caspase-3 and eukaryotic translation initiation factor 2α phosphorylation were increased, along with evidence of increased autophagy. These results suggest that human angiomyolipoma cells are uniquely susceptible to agents that exacerbate ER stress and that additional synergy may be achievable with targeted combination therapy.
Authors:
Brian J Siroky; Hong Yin; Justin T Babcock; Lu Lu; Anna R Hellmann; Bradley P Dixon; Lawrence A Quilliam; John J Bissler
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-07-11
Journal Detail:
Title:  American journal of physiology. Renal physiology     Volume:  303     ISSN:  1522-1466     ISO Abbreviation:  Am. J. Physiol. Renal Physiol.     Publication Date:  2012 Sep 
Date Detail:
Created Date:  2012-09-17     Completed Date:  2012-12-26     Revised Date:  2013-09-30    
Medline Journal Info:
Nlm Unique ID:  100901990     Medline TA:  Am J Physiol Renal Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  F831-44     Citation Subset:  IM    
Affiliation:
Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, OH 45229-3039, USA. john.bissler@cchmc.org
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MeSH Terms
Descriptor/Qualifier:
Angiomyolipoma / etiology,  genetics,  metabolism*
Antineoplastic Agents / pharmacology
Apoptosis / drug effects,  physiology
Caspase 3 / metabolism
Cell Line, Tumor
Endoplasmic Reticulum Stress*
Eukaryotic Initiation Factor-2 / metabolism
Humans
Immunosuppressive Agents / pharmacology
Kidney Neoplasms / etiology,  genetics,  metabolism*
Leupeptins / pharmacology
Phosphorylation
Poly(ADP-ribose) Polymerases / metabolism
Proteasome Inhibitors / pharmacology
Proteins / metabolism
Sirolimus / analogs & derivatives,  pharmacology
Transcription Factor CHOP / metabolism
Transfection
Tuberous Sclerosis / complications*,  genetics,  metabolism
Tumor Suppressor Proteins / genetics,  metabolism*
Grant Support
ID/Acronym/Agency:
2T32-ES-7250-21A1/ES/NIEHS NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Eukaryotic Initiation Factor-2; 0/Immunosuppressive Agents; 0/Leupeptins; 0/Proteasome Inhibitors; 0/Proteins; 0/Tumor Suppressor Proteins; 0/mechanistic target of rapamycin complex 1; 133407-82-6/benzyloxycarbonylleucyl-leucyl-leucine aldehyde; 147336-12-7/Transcription Factor CHOP; 159351-69-6/everolimus; 4JG2LF96VF/tuberous sclerosis complex 2 protein; 53123-88-9/Sirolimus; EC 2.4.2.30/Poly(ADP-ribose) Polymerases; EC 3.4.22.-/Caspase 3
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