Chaperones and protein quality control in the neoplastic process

Maintenance of proteome quality control in cells is a vital and extremely complex task, which requires fine-tuning among synthesis, folding, and degradation of proteins and is controlled by an integrated network of subcellular components. A pivotal role in this process is played by chaperones, molecular machines that take part in nearly all cellular functions and make possible the optimal activity of proteins by assisting their folding, conformational changes, and subcellular trafficking, and by controlling protein degradation following unfolding, misfolding, or aggregation. Neoplastic cells undergo major changes in the homeostasis of their proteome, or proteostasis, as a consequence of a profound rewiring of their metabolic circuitries and of exposure to stressful environmental stimuli, such as hypoxia or nutritional and pH fluctuations. These stress conditions also affect protein folding in the endoplasmic reticulum and mitochondrial bioenergetic functions, leading to activation of organelle-restricted, protective signalling pathways called unfolded protein responses, which can subtly regulate the equilibrium among death, dormancy, and aggressiveness of tumour cells. In most cancer types molecular chaperones are overexpressed and exploited to cope with these stress stimuli and to underpin pro-oncogenic biological routines, including cell growth, proliferation, invasion, metastasis, and escape to death stimuli. Chaperone induction has been associated with cancer progression, resistance to chemotherapy, and poor prognosis; therefore, development of chaperone-targeting drugs has emerged as a promising antineoplastic strategy.