Chaperones in stress-tolerance and cancer survival
Over the years organisms have developed systems to react to external insults perturbing normal cell homeostasis. One of the most conserved and studied of these systems is represented by the heat shock response, a mechanism first characterized as the reaction of cells to sudden increase of temperature1. This kind of response allows cell survival in otherwise stressful conditions like exposure to heavy metals, lack of oxygen and nutrients, radiation and metabolic inhibitors. The characteristic feature of this system is the increased expression of a specific set of proteins termed the heat shock proteins or molecular chaperones2. The physiological role of this class of proteins is to prevent protein aggregation and misfolding during stress3, to regulate folding of nascent polypeptides4 and to drive misfolded proteins to the proteasomal machinery for degradation5. In addition, the molecular chaperones play a role in gene expression, DNA replication, cell differentiation and proliferation, senescence, apoptosis and immortalization involving pathways crucial for embryonic development, cell homeostasis and cancer progression6.
A group of non-client proteins termed co-chaperones binds the molecular chaperones to modulate their activity. These proteins have functions ranging from enhancing the enzymatic activity to the formation of multicomplexes and the choice of specific client proteins for the chaperones11.
Chaperones and co-chaperones are overexpressed in many tumours such as breast7, colon8 and prostate9 and are associated with poor prognosis and chemotherapy resistance neoplasia10.
Why Prostate Cancer
Prostate cancer (PCa) is the most common type of cancer in men. The Federal Cancer Surveillance Unit at the Robert Koch Institute estimates that in Germany prostate cancer affects 26.2% of male population, killing 30.000 men a year (10% of cancer-related death among men). Death of PCa patients is mostly due to the development of resistance of the tumour to chemotherapy. At this stage, prostate cancer is considered not curable yet and is therefore important to understand the mechanisms leading to resistance and to find new therapeutical strategies.
The aims of this lab are
- Studying the interplay between chaperones and co-chaperones leading to prostate cancer cell proliferation and survival.
- Designing new therapeutical compounds aiming to interfere with the chaperone/co-chaperone system.
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11 Caplan, A. J., What is a co-chaperone? Cell Stress Chaperones 8 (2), 105 (2003).