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Esposito MiP2010

From Bioblast
Laudiero G, Maddalena F, Amoroso MR, Piscazzi A, Landriscina M, Esposito F (2010)

Link: Abstracts Session 4

Laudiero G, Maddalena F, Amoroso MR, Piscazzi A, Landriscina M, Esposito F (2010)

Event: MiP2010

TNF receptor-associated protein 1(TRAP1), a mitochondrial chaperone with antioxidant and antiapoptotic functions [1,2], is involved in multi-drug resistance of human colorectal carcinoma cells [3]. TRAP1 protein levels are increased in colorectal carcinoma cells resistant to several anti-tumor agents and in the majority of human colorectal cancers. Recent studies demonstrated that TRAP1 can be proposed as a novel molecular target in localized and metastatic prostate cancer [4] and some other tumours [5], but little is known about TRAP1 signal transduction: Kang et al identified TRAP1 as a member of a cytoprotective network selectively active in mitochondria of tumor tissues [6]. Starting from this limited information, a proteomic analysis of TRAP1 co-immunoprecipitation complexes was performed in our laboratory in order to further characterize the TRAP1 network and evaluate protein interactors relevant for TRAP1 role in multidrug resistance.


Labels: Pathology: Cancer 

Organism: Human 






Full text

TNF receptor-associated protein 1(TRAP1), a mitochondrial chaperone with antioxidant and antiapoptotic functions [1,2], is involved in multi-drug resistance of human colorectal carcinoma cells [3]. TRAP1 protein levels are increased in colorectal carcinoma cells resistant to several anti-tumor agents and in the majority of human colorectal cancers. Recent studies demonstrated that TRAP1 can be proposed as a novel molecular target in localized and metastatic prostate cancer [4] and some other tumours [5], but little is known about TRAP1 signal transduction: Kang et al identified TRAP1 as a member of a cytoprotective network selectively active in mitochondria of tumor tissues [6]. Starting from this limited information, a proteomic analysis of TRAP1 co-immunoprecipitation complexes was performed in our laboratory in order to further characterize the TRAP1 network and evaluate protein interactors relevant for TRAP1 role in multidrug resistance.

Through a proteomic analysis of TRAP1 co-immunoprecipitation complexes, the Ca2+-binding protein Sorcin was identified as a new TRAP1 interactor. This result prompted us to further investigate the presence and role of Sorcin in the mitochondria of human colon carcinoma cells. Using fluorescence microscopy and western blot analysis of purified mitochondria and sub-mitochondrial fractions, we demonstrated the mitochondrial localization of an isoform of Sorcin with an electrophoretic motility lower than 20 kDa that specifically interacts with TRAP1. Furthermore, the effects of overexpressing or down-regulating Sorcin and/or TRAP1 allowed us to demonstrate a reciprocal regulation between these two proteins and to show that their interaction is required for Sorcin mitochondrial localization and TRAP1 stability. Indeed, the depletion of TRAP1 by shRNA in colorectal carcinoma cells lowered Sorcin levels in mitochondria, whereas the depletion of Sorcin by siRNA increased TRAP1 degradation. We also report several lines of evidence suggesting that intramitochondrial Sorcin plays a role in TRAP1 cytoprotection. Finally, preliminary evidence that TRAP1 and Sorcin are both implicated in multi-drug resistance and are co-upregulated in human colorectal carcinomas is provided.

These novel findings highlight a new environment for Sorcin, opening the possibility that some cytoprotective functions previously described for this protein could be explained by its involvement in mitochondrial metabolism and participation in the TRAP1 pathway.

1. Montesano Gesualdi N, Chirico G, Pirozzi G, Costantino E, Landriscina M, Esposito F (2007) Tumor necrosis factor-associated protein 1 (TRAP-1) protects cells from oxidative stress and apoptosis. Stress 10: 342-350.

2. Landriscina M, Maddalena F, Laudiero G, Esposito F (2009) Adaptation to oxidative stress, chemoresistance, and cell survival. Antioxid. Redox Signal 11: 2701-2716.

3. Costantino E, Maddalena F, Calise S, Piscazzi A, Tirino V, Fersini A, Ambrosi A, Neri V, Esposito F, Landriscina M (2009) TRAP1, a novel mitochondrial chaperone responsible for multi-drug resistance and protection from apoptosis in human colorectal carcinoma cells. Cancer Lett. 279: 39-46.

4. Leav I, Plescia J, Goel HL (2009) Cytoprotective mitochondrial chaperone TRAP-1 as a novel molecular target in localized and metastatic prostate cancer. Am. J. Pathol. 176: 393-401.

5. Fang W, Li X, Jiang Q, Liu Z, Yang H, Wang S (2008) Transcriptional patterns, biomarkers and pathways characterizing nasopharyngeal carcinoma of Southern China. Transl. Med. 6: 32.

6. Kang BH, Plescia J, Dohi T, Rosa J, Doxsey SJ, Altieri DC (2007) Regulation of tumor cell mitochondrial homeostasis by an organelle-specific Hsp90 chaperone network. Cell 131: 257-270.