Proteomics: a strategy to understand the novel targets in protein misfolding and cancer therapy

Abstract

Proteins carry out important functions as they fold themselves. Protein misfolding occurs during different biochemical processes and may lead to the development of diseases such as cancer, which is characterized by genetic instability. The cancer microenvironment exposes malignant cells to a variety of stressful conditions that may further promote protein misfolding. Tumor development and progression often arises from mutations that interfere with the appropriate function of tumor-suppressor proteins and oncogenes. These may be due to alteration of catalytic activity of the protein, loss of binding sites for effector proteins or alterations of the native folded protein conformation. Src family kinases, p53, mTOR and C-terminus of HSC70 interacting protein (CHIPs) are some examples associated with protein misfolding and tumorigenesis. Molecular chaperones, such as heat-shock protein (HSP)70 and HSP90, assist protein folding and recognize target misfolded proteins for degradation. It is likely that this misfolding in cancer is linked by common principles, and may, therefore, present an exciting possibility to identify common targets for therapeutic intervention. Here we aim to review a number of examples that show how alterations in the folding of tumor-suppressor proteins or oncogenes lead to tumorigenesis. The possibility of targeting the targets to repair or degrade protein misfolding in cancer therapy is discussed.

Figure 1. Model of protein misfolding and therapeutic targets in cancer

Proteins are synthesized on ribosomes from the genetic information encoded in cellular DNA and undergo the major part of their folding in the cytoplasm after release from the ribosome. Newly synthesized proteins are translocated into the endoplasmic reticulum, where they fold into their 3D structures. Correctly folded proteins are transported to the Golgi complex and then delivered to the extracellular environment. Under certain circumstances, a folded protein is converted to a misfolded protein by various stresses, gene mutations or proteolysis. During normal conditions, misfolded proteins are detected by a quality-control mechanism and are degraded by the ubiquitin–proteosome pathway. A misfolded protein can be induced to form prefibrillar oligomers at higher concentrations and transported to form aggresomes. These aggregated proteins at the aggresome are targeted for degradation via macroautophagy. Accumulation of prefibrillar oligomers at the aggresome pathway may induce apoptosis. Curcumin, a potential antioxidant or anticancer compound may inhibit protein misfolding and/or aggregation. Protein aggregation can also be blocked by upregulation of molecular chaperones with heat shock protein (HSP)90 inhibitors (17-allylamino-demethoxygeldanamycin (AAG), 17-[dimethylaminoethylamino]-17-demethoxygeldanamycin (DMAG), STA-9090, STA-1474 and geldamycin) or HSP70 inhibitors, such as 2-phenylethyneusulfonamide. Aggregate clearance can be upregulated via inhibition of mTOR by rapamycin that inhibits macroautophagy. Analogues of rapamycin, such as CCI-779 (temsirolimus), RAD001 (everolimus) and AP23573, are likely to be the first mTOR-perturbing molecules to be approved for anticancer use in humans. Redrawn with permission of Cambridge University Press from [106].