Cells have evolved a number of coping mechanisms to enhance survival during periods of stress. Activation of these stress response mechanisms serves as a key determinant of a cell’s ability to survive and adapt to the stress event, or whether cell death pathways such as apoptosis are activated. These mechanisms include the heat shock response mediated primarily via the action of the transcription factor HSF1, or the unfolded protein response (UPR) activated as a result of the accumulation of misfolded proteins within the endoplasmic reticulum. As well as regulating cell death it has recently been established that these pathways also have a central role in enabling the proliferation and survival of cancer cells. We are particularly interested in understanding the molecular events associated with increased activity of these stress responses during cancer progression and how these might be modulated for therapeutic benefit. In addition we are investigating modulation of the proteasome as a potential therapy for treatment of colon cancer.
Modulation of the heat shock response:
The heat shock response mediated via the transcription factor HSF1 is a potent survival mechanism that results in the increased expression of cytoprotective molecular chaperone proteins such as Hsp90, 70 and 27. Increased expression of Hsps has been demonstrated in several cancer types and has been correlated to poor survival and resistance to therapy. Furthermore, recent evidence suggests that HSF1 is a potent regulator of cancer cell survival and proliferation in a number of tumour models. In this project we are investigating ways to modulate the function of HSF1 in colon cancer cells, and examining the effects on downstream signalling cascades in order to identify the molecular means by which HSF1 mediates it effects, and identify potential new therapeutic targets. Furthermore, we are interested in examining the potential of HSF1 inhibitors to enhance sensitivity to standard and also more novel chemotherapeutic agents. As chemoresistance is one of the current bottlenecks of cancer therapy we hope to identify new combinations of drugs to overcome the acquisition of chemoresistance.
Targeting the proteasome in cancer cells:
Cancer cells have enhanced susceptibility to inhibitors of the proteasome, a phenomenon that has been recently exploited with the utilisation of the proteasome inhibitor, bortezomib, for the treatment of multiple melanoma. In previous work we have identified differential regulation of Rpt4, a component of the 19S regulatory subunit of the proteasome, in tumour tissue from colorectal cancer patients (McCawley et al.). Using both in vitro and in vivo systems we are investigating the role of this protein in the growth and survival of cancer cells and addressing whether it is a suitable target for future therapeutic intervention.
McCawley N, Conlon S, Hector S, Cummins RJ, Dicker P, Johnston PG, Kay EW, McNamara DA, Prehn JH and Concannon CG (2012). Analysis of proteasomal subunit expression reveals Rpt4 as a prognostic marker in stage II colorectal cancer. Int J Cancer. 131: E494-500.
Concannon CG, Koehler BF, Reimertz C, Murphy BM, Bonner C, Thurow N, Ward MW, Kögel D and Prehn JHM (2007) Apoptosis induced by proteasome inhibition in cancer cells: predominant role of the p53/PUMA pathway. Oncogene. 26:1681-1692.