Lysosomes in cancer-living on the edge (of the cell)

Abstract

The lysosomes have definitely polished their status inside the cell. Being discovered as the last resort of discarded cellular biomass, the steady rising of this versatile signaling organelle is currently ongoing. This review discusses the recent data on the unconventional functions of lysosomes, focusing mainly on the less studied lysosomes residing in the cellular periphery. We emphasize our discussion on the emerging paths the lysosomes have taken in promoting cancer progression to metastatic disease. Finally, we address how the altered cancerous lysosomes in metastatic cancers may be specifically targeted and what are the pending questions awaiting for elucidation.

Figure 1

Lysosomal functions in cancer cells. Endocytosis targets extracellular matrix (ECM) components, cell surface receptors and cell-cell adhesion components to lysosomal degradation and/or recycling back to plasma membrane (PM). The worn-out cellular macromolecules and damaged organelles are targeted to autophagosomes (AP). When nutrients are available, mTORCl kinase is activated at the lysosomal membrane in the cell periphery; during low nutrient conditions, kinase activity is lowered and lysosomes accumulate in juxtanuclear compartment. Lysosomal calcium release via MCOLN1 activates TFEB via calcineurin phosphatase activity and induces TFEB translocation to nucleus to activate transcription. Bone resorption by enzymes in osteoclasts involves polarized accumulation of lysosomes and lysosomal acidification of facilitate bone resorption. In lysosomal exocytosis Involving calcium flux, lysosomes fuse with the plasma membrane and release hydrolases to the cell exterior. Oncogenic activation leads to lysosomal localization to the cellular periphery, increased release of hydrolases to the extracellular compartment which enables ECM degradation and invasion; oncogenic activation can lead to lysosomal membrane destabilization and to altered cell death responses.

Figure 2

Lysosomes in cellular adhesions and In invasion. Lysosomes/late endosomes (L/LE) reach the periphery via MT plus –end mediated traffic and with the help of kinesins, Arl8b, BORC and other effector molecules (RhoA, PI3Ks, FYCO, not shown in figure). BORC regulates Arl8b recruitment to lysosomal membranes and drives KIF-l-dependent motility. At focal adhesions (FA), the LAMTOR2/3 in late endosomes facilitates the removal of IQ.GAP from the adhesions thus promoting cell motility. Cathepsins Z, H, B and G activate focal adhesion molecules FAK, Src and integrin-binding protein talin: Cathepsin Z and H promote thereby tumor invasion into extracellular matrix (ECM) whereas cathepsin B promotes invasion in rheumatoid arthtritis and neutrophil cathepsin G affects myocyte survival. In osteoclasts, the Racl-assisted traffic of lysosomes to actin-rich integrin adhesions creates an acidic microenvironment, involving V-ATPase and chloride channels, inside which cathepsin K and matrix metalloproteinases degrade the bone matrix. Cathepsin B localization to and release from lipid rafts promotes cancer progression. Lysosomal traffic towards MTOC is driven by dynein-dynactin complex, Rab7 GTPase and several other molecules (RILP, Rabip4’, AP-3, Huntingtin (Htt) and GTPases Rab34 and Rab36, not shown in figure). Additionally, integrin uptake and release from lysosomes back to the plasma membrane, with the help of Rab25 GTPase and CLIC3, contributes to carcinoma invasion.