Unraveling the mechanisms involved in acetate induced apoptosis in colorectal cancer

Cathepsin D has garnered increased attention in recent years, mainly since it has been associated with several human pathologies. In particular, cathepsin D is often overexpressed and hypersecreted in cancer cells, implying it may constitute a therapeutic target. However, cathepsin D can have both antiand pro-survival functions depending on its proteolytic activity, cellular context and stress stimulus. Therefore, a more detailed understanding of cathepsin D regulation and how to modulate its apoptotic functions is clearly needed. In this review, we provide an overview of the role of cathepsin D in physiological and pathological scenarios. We then focus on the opposing functions of cathepsin D in apoptosis, particularly relevant in cancer research. Emphasis is given to the role of the yeast protease Pep4p, the vacuolar counterpart of cathepsin D, in life and death. Finally, we discuss how insights from yeast cathepsin D and its role in regulated cell death can unveil novel functions of mammalian cathepsin D in apoptosis and cancer. Yeast as a tool to explore cathepsin D function H. Pereira 1 , C.S. F. Oliveira 1,2 , L. Castro 1 , A. Preto 1 , S. R. Chaves 1,# , M. Côrte-Real 1,#, * 1 CBMACentre of Molecular and Environmental Biology. Department of Biology, University of Minho, Campus de Gualtar, 4710-057, Braga, Portugal. 2 ICBAS Institute of Biomedical Sciences Abel Salazar, University of Porto, 4050-313, Porto, Portugal. # These senior authors contributed equally to this article. * Corresponding Author: M Côrte-Real, CBMA (Centre of Molecular and Environmental Biology); Department of Biology, University of Minho, Campus de Gualtar; 4710-057 Braga, Portugal; Tel: +351 253604314; E-mail: mcortereal@bio.uminho. pt CATHEPSINS Cathepsins are members of a large protease family, which can be subdivided according to their structure and activesite amino acid into cysteine (cathepsins B, C, F, H, K, L, O, S, V, W, and X), serine (cathepsins A and G), and aspartic cathepsins (cathepsins D and E). While cathepsins B, L, H, C and D are ubiquitously expressed in human tissues, expression of cathepsins A, G, K, S, V, X and W is tissue and cell type specific [1-4]. In general, cathepsins are found in acidic cellular organelles, lysosomes and endosomes. Initially, their function was thought to be limited to bulk degradation of proteins delivered to the lysosome by endocytosis or autophagocytosis. However, it was later demonstrated that cathepsins possess highly specific and directed proteolytic activity, and that they can be found in other cellular compartments [5-10]. Numerous physiological functions of cathepsins have been uncovered, including a role in hormone and antigen processing, bone and tissue remodeling, growth factor and proenzyme activation and, more recently, in the immune response [5, 6, 11-13]. Cathepsins also participate in apoptosis and are translocated from the lysosomal lumen to the cytosol of mammalian cells through lysosomal membrane permeabilization (LMP) in response to a variety of apoptotic signals [14-16]. These lysosomal proteases can also be secreted from the cell and degrade extracellular matrix proteins such as collagen, fibronectin, proteoglycans and laminin [17]. In addition to their physiological function, cathepsins have also been associated with several pathologies such as cardiovascular diseases, osteoporosis, rheumatoid arthritis, atherosclerosis and cancer [6, 11, 17-19]. Elucidating the mechanisms underlying the involvement of cathepsins in the pathogenesis of these diseases, and how they can be modulated to develop new prevention and therapeutic strategies, has therefore taken center stage. Among cathepsins, cathepsin D (CatD) has attracted increased attention in recent years due to its importance in the mediation of lysosomal cell death pathways and in cancer. In this review, we will concentrate on both physiological and pathological functions of CatD, as well as on yeast as a model system to study CatD pathophysiology. ROLE OF CATHEPSIN D IN CELLULAR PHYSIOLOGY AND PATHOLOGY CatD is a soluble aspartic endopeptidase found in the lysosomes of most mammalian cells. Like other cathepsins, doi: 10.15698/mic2015.07. 212 Received originally: 31.12. 2014; in revised form: 30.04. 2015, Accepted 12.05. 2015 Published 11.07. 2015.