Supervisor: Dr Michelangelo Campanella (RVC, UCL Consortium for Mitochondrial Research)
Co-Supervisor: Dr Andreas Schatzlein (SoP), Dr Brian Catchpole (RVC)
It is now established that anticancer treatment will be improved by molecular therapy. The new generation of molecular targeted anticancer drugs (eg. Gleevec) thus holds the promise of efficacious and highly specific therapeutics. Based on these insights, it has become clear that the best targets are molecules occupying central nodes in essential signalling network thus integrating upstream pathways. Good prototypes are therefore mitochondrial targets as the organelle's commitment to apoptosis is relevant to all types of cancer and defines cancer cells susceptibility to chemotherapy.
Critical for the mitochondrial energetic balance and induction of apoptosis are the Voltage Dependent Anion Channels (VDACs). Localized on the outer mitochondrial membrame, VDACs regulate mitochondrial Ca2+ homeostasis, ATP rationing, oxidative stress and triggering of apoptosis.
VDACs performance appears to be regulated by the relative expression level of the mitochondrial Translocator Protein mTSPO co-localised in the outer mitochondrial membrame.
The increased levels of mTSPO are thought to inhibit VDACs channel opening, thus down-regulating mitochondrial metabolism and suppressing apoptosis. We have been able to show in human cancer cells that down-regulation of mTSPO increases mitochondrial Ca2+ and cytosolic ATP and facilitates Ca2+ mediated apoptosis. Increased apoptosis is recorded also in presence of the mTSPO pharmacological inhibitor PK11195 which also upregulates mitochondrial Ca2+. mTSPO appears therefore a suitable therapeutic target in all types of cancer and PK11195 a promising anticancer drug candidate for this molecule.
This project is an ideal opportunity for someone interested in cancer biology and cutting edge approaches for molecular therapy. Insights of molecular biology and biochemistry are appreciated and interest for imaging and luminescent based approaches for cell physiology would be advantageous.
Key References
1. Campanella, M., Pinton, P., Rizzuto, R. (2004) Mitochondrial Ca2+ homeostasis in health and disease. Biol Res. 37(4): 653-60
2. Chami, M., Prandini, A., Campanella, M., Pinton, P., Szabadkai, G., Reed JC., Rizzuto, R. (2004) Bcl-2 and Bax exert opposing effects on Ca2+ signaling, which do not depend on their putative pore-forming region. J Biol Chem. 279(52):54581-9.
3. Han, Z. et al. (2003) Expression of peripheral benzodiazepine receptor (PBR) in human tumors: relationship to breast, colorectal and prostate tumor progression. J. Recept. Signal. Transduct. Res. 23, 225-238.
4. Campanella, M. et al. (2008) Modulation of intracellular Ca2+ signalling in HeLa cells by the apoptotic cell death enhancer PK11195. Biochem. Pharmacol. 76, 1628-1636.
Further details about the project may be obtained from:
Supervisor: Dr Michelangelo Campanelloa, mcampanella@rvc.ac.uk
Co-Supervisor: Dr Andreas Schatzlein, andreas.schatzlein@pharmacy.ac.uk
Further information about PhDs at the Royal Veterinary College is available from:
http://www.rvc.ac.uk/Postgraduate/PhD/ThemesAndGroups.cfm
Application forms and details about how to apply are available from:
http://www.rvc.ac.uk/Postgraduate/Documents/PG08_forms.pdf
The Graduate School
Royal Veterinary College
Royal College Street
London
NW1 0TU
UK
Tel: 00 44 (0) 20 7468 5134
Fax: 00 44 (0) 7468 5060
E-mail: graduateschool@rvc.ac.uk
To apply, please send a completed Postgraduate Application Form (http://www.rvc.ac.uk/Postgraduate/Documents/PG08_forms.pdf) to the Registrar at the above address.
Closing date for application: 1 March 2010