Abstract B73: Proteostasis network modules as molecular targets for cancer therapeutics.
Authors: Komseli Eirini-Stavroula , Sesti Fabiola , Evangelou Konstantinos , Cheimonidou Christina , Kotsinas Athanassios , Gorgoulis Vassilis , Trougakos Ioannis P. 
Published: August 2014

Abstract
The maintenance of biomolecules functionality is essential for the assurance of cellular homeostasis. At the proteome level this is achieved by the action of a modular, yet integrated subcellular compartment-specific system which ensures proteome quality control and it is called the proteostasis network (PN). PN is orchestrated by a plethora of different mechanisms and complex protein machines aiming to respond to stressors, recognize and either rescue (via the action of chaperones) or degrade unfolded, misfolded or damaged polypeptides at the two main cellular proteolytic systems, namely the proteasome and the lysosome. We have found that aging is accompanied by increased proteotoxic stress and a reduction of PN modules functionality. Interestingly, proteotoxic stress is also an emerging hallmark of age-related diseases, including tumorigenesis, and we recently proposed that age-related disruption of proteostasis contributes to tumor formation by (among others) increasing genomic instability due to reduced fidelity in processes like DNA replication or repair. We also hypothesized that the carcinogenesis-related increasing proteome instability eventually triggers the reactivation of the PN modules at advanced and/or metastatic stages in order for the tumor to survive and enable its various malignant phenotypes. We are testing these hypotheses by examining the differential regulation of PN components in precancerous and cancerous lesions of tumor biopsies, as well as, in cellular models of step-wise carcinogenesis. Specifically, precancerous and cancerous lesions of the larynx along with normal epithelium were examined by immunohistochemical staining for the expression levels of Apolipoprotein J/Clusterin (CLU); a molecular chaperone that has been implicated in tumor formation, metastasis and tumor cells resistance to chemotherapeutic drugs. Additionally, human bronchial epithelial cells into which various oncogenes were sequentially introduced, as well as, a mouse skin carcinogenesis model have been used to: a) investigate the status of PN components as a response to oncogenic hits and, b) to test the differential sensitivity of tumor vs. normal cells to stressors and to PN modules inhibitors. We found that CLU expression is induced by de novo synthesis in larynx dysplasia. In support, at both human and mouse cellular models of carcinogenesis we noted higher levels and activities of PN modules in advanced tumorigenesis; these phenotypes were accompanied with increased oxidative damage and proteome instability. Interestingly, advanced and/or metastatic mouse tumor cells were more sensitive to disruption of proteostasis (e.g. proteasome inhibition) or increased oxidative load compared to normal cells, while combined proteasome and lysosomal inhibition further sensitized metastatic tumor cells. These observations indicate that while tumor evolves over a cellular landscape of increased proteome instability, tumor cells eventually become “addicted” to higher activities of the PN modules in order to survive. Thus, inhibition of PN components provides a strategy for the development of novel tumor specific therapies. We are currently investigating this option by screening for natural compounds functioning as potent inhibitors of PN modules.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B73.
Citation Format: Eirini-Stavroula Komseli, Fabiola Sesti, Konstantinos Evangelou, Christina Cheimonidou, Athanassios Kotsinas, Vassilis Gorgoulis, Ioannis P. Trougakos. Proteostasis network modules as molecular targets for cancer therapeutics. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B73.