'Patchiness' and basic cancer research: unravelling the proteases

Abstract

The recent developments in Cathepsin protease research have unveiled a number of key observations which are fundamental to further our understanding of normal cellular homeostasis and disease. By far, the most interesting and promising area of Cathepsin biology stems from how these proteins are linked to the fate of living cells through the phenomenon of Lysosomal Leakage and Lysosomal Membrane Permeabilisation. While extracellular Cathepsins are generally believed to be of central importance in tumour progression, through their ability to modulate the architecture of the Extracellular Matrix, intracellular Cathepsins have been established as being of extreme significance in mediating cell death through Apoptosis. With these two juxtaposed key research areas in mind, the focus of this review highlights recent advancements in how this fast-paced area of Cathepsin research has recently evolved in the context of their mechanistic regulation in cancer research. Abbreviations : ECM, Extracellular Matrix; MMP, Matrix Metalloproteases; LL, Lysosomal Leakage; LMP, Lysosomal Membrane Permeabilisation; LMA, Lysosomorphic Agents; BC, Breast Cancer; ASM, Acid Sphingomyelinase; TNF-α, Tumor Necrosis Factor-alpha; LAMP, Lysosomal Associated membrane Protein; PCD, Programmed Cell Death; PDAC, Pancreatic Ductal Adenocarcinoma; ROS, Reactive Oxygen Species; aa, amino acids.

Keywords: Cathepsin; Cystatins; apoptosis; cancer; lysosome; metastasis.

Figure 1.

Schematic showing the synthesis, trafficking and maturation of Cathepsin proteins in normal cells (green arrows) and cancer cells (red arrows). Pro Cathepsin mRNAs are translated, inserted into the Endoplasmic Reticulum where they are glycosylated and transported to the Golgi network. Upon further glycosylation, they are transported in a Mannose-6-Phosphate (M-6-P)-dependent manner to the late Endomes after which they can enter the Perinuclear Lysosome or the Peripheral Lysosome and be secreted to modulate the Extracellular Matrix (ECM, red arrows).

Figure 2.

Lysosomal Membrane Permeability (LMP) and Lysosomal Leakage (LL) determine cell survival based on the cellular expression levels of Heat Shock Proteins (HSP), Cystatins, anti-oxidants, Sphingomyelin, Cholesterol, LAMP1/2 and Bcl-2. Cell death can also be induced by the lysosome, based upon cellular levels of Reactive Oxidative Species (ROS), Cathepsin, Lysosomorphic Agents, Lysosomal Leakage, Microtubule Disrupting drugs, Viral Proteins, Toxins, Lipids and Metabolites, protein p53 and protein BID (see text for more details).

Figure 3.

Schematic showing the events leading to Cathepsin protein release (green arrows) following the induction of Lysosomal Membrane Permeabilisation (LMP) and Lysosomal Leakage (LL) which result in apoptosis, through Mitochondrial Outer Membrane Permeabilization (MOMP) and Poly (ADP-ribose) polymerase (PARP) activation (red arrows) via Caspases-3 and −9. The blue arrows highlight enhanced apoptosis through the activity of Cathepsin-mediated cleavage of anti-apoptosis proteins (see text for more details).

Figure 4.

Schematic highlighting the regulatory inter-relationships between transcription factors, micro-RNAs (mir), Cytokine/Chemokine signalling, Cathepsin inhibitors and signalling intermediates, DNA repair and cell cycle regulators and trafficking proteins with Cathepsin gene regulation, protein trafficking and secretion (see text for details).