Abstract
The endolysosomal system (ES) consists of lysosomes; early, late, and recycling endosomes; and autophagosomes. It is a key regulator not only of macromolecule degradation and recycling, plasma membrane repair, homeostasis, and lipid storage, but also of antigen presentation, immune defense, cell motility, cell death signaling, tumor growth, and cancer progression. In addition, it plays a critical role in autophagy, and the autophagy-lysosome pathway is intimately associated with the hallmarks of cancer, such as escaping cell death pathways, evading immune surveillance, and deregulating metabolism. The function of endolysosomes is critically dependent on both soluble and endolysosomal membrane proteins such as ion channels and transporters. Cation channels found in the ES include members of the TRP (transient receptor potential) channel superfamily, namely TRPML channels (mucolipins) as well as two-pore channels (TPCs). In recent studies, these channels have been found to play crucial roles in endolysosomal trafficking, lysosomal exocytosis, and autophagy. Mutation or loss of these channel proteins can impact multiple endolysosomal trafficking pathways. A role for TPCs in cancer cell migration and metastasis, linked to distinct defects in endolysosomal trafficking such as integrin trafficking, has been recently established. In this review, we give an overview on the function of lysosomes in cancer with a particular focus on the roles which TPCs and TRPML channels play in the ES and how this can affect cancer cells.
Highlights
In Europe and the USA, cancer and cancer-related diseases account for about 25–30% of deaths
Interfering with lysosomal function by the inhibition of the vacuolar H+-ATPase, which is essential for lysosomal acidification, was recently demonstrated to abrogate excessive epidermal growth factor receptor (EGFR) and Ras signaling in cancer cells, leading to reduced migration and proliferation [26,27]
TRPMLs and two-pore channels (TPCs) have been found to be involved in mammalian target of rapamycin (mTOR) signaling, autophagy, and EGF/EGFR as well as integrin trafficking
Summary
In Europe and the USA, cancer and cancer-related diseases account for about 25–30% of deaths. Targeting the lysosome has emerged as an increasingly attractive strategy in cancer therapy in recent years [1,2,3]. That links exist between cancer and lysosomal function is not new. It has already been postulated decades ago that an increased liberation of lysosomal hydrolases in tumors could contribute to inflammatory and toxic effects and could promote the detachment of cells from tumor masses and facilitate metastatic spread. The oncogenic intracellular ion channels comprise mitochondrial channels such as Kv1.3 (KCNA3), IKCa (KCNN4), and TASK-3, among others, in addition to the intracellular chloride channel CLIC-4 or different TRP (transient receptor potential) channels, e.g., TRPM8 and TRPC1 (for excellent recent reviews see e.g., [8,9]; for other TRP channels in relation to cancer see e.g., [10,11]).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
