Two-Pore Channel Function Is Crucial for the Migration of Invasive Cancer Cells

Abstract

Metastatic invasion is the major cause of cancer-related deaths. In this study, we introduce two-pore channels (TPC), a recently described class of NAADP- and PI(3,5)P2-sensitive Ca-permeable cation channels in the endolysosomal system of cells, as candidate targets for the treatment of invasive cancers. Inhibition of the channel abrogated migration of metastatic cancer cells Silencing or pharmacologic inhibition of the two-pore channel TPC2 reduced lung metastasis of mammary mouse cancer cells. Disrupting TPC function halted trafficking of β1-integrin, leading to its accumulation in EEA1-positive early endosomes. As a consequence, invasive cancer cells were no longer able to form leading edges, which are required for adequate migration. Our findings link TPC to cancer cell migration and provide a preclinical proof of concept for their candidacy as targets to treat metastatic cancers..

The protein interaction networks of mucolipins and two-pore channels

“…Similarly, further investigations of described interactors must be carried out before drawing final conclusions of their importance in a TPC/TRPML-associated context. Taken together, this review underscores the potential held by TPC/TRPML as future therapeutic targets to treat currently incurable diseases, while identifying approaches necessary to elucidate the multifaceted roles of these endolysosomal, non-selective cation channels [12,[22][23][24][25][29][30][31]. [60].…”

“…TRPML channels are widely accepted to be Ca 2+ permeable, yet the recent discovery of NAADP-activated TPC-mediated Ca 2+ currents remains heavily debated, as at least two groups claim that TPCs are predominantly Na + permeable channels activated by PI(3,5)P 2 , while several other groups show that TPCs are also Ca 2+ permeable and can be activated by both PI(3,5)P 2 and NAADP [15][16][17][18][19][20][21]. Resolution of these ongoing debates is of particular importance, as the channels are proposed therapeutic targets to treat disorders such as cancer [22,23], neurodegeneration [24][25][26][27], metabolic/cardiovascular disorders [12,28], and infectious diseases [29][30][31][32].…”

Targeting Intracellular Calcium Signaling ([Ca2+]i) to Overcome Acquired Multidrug Resistance of Cancer Cells: A Mini-Overview

“…Anguita and Villalobo described in 2016 that there is a crosstalk between non-receptor Src-family kinases and the Ca 2+ transient generated in activated cells by a variety of extracellular and intracellular stimuli that might result in stimulation of signaling pathways [53]. Nguyen et al (2017) shows that two-pore channels, a class of NAADP- and PI(3,5)P2-sensitive Ca 2+ -permeable cation channels in the endolysosomal system of cells, are linked to cancer cell migration and might represent future targets to treat metastatic cancers [54]. …”

Mining of Ebola virus entry inhibitors identifies approved drugs as two-pore channel pore blockers

“…Local Ca 2+ fluxes through TPCs are increasingly implicated in membrane trafficking events [10,11]. These include roles for TPCs in regulating lysosome morphology [12], retrograde transport between late endosomes and the Golgi [13], and endocytic trafficking of receptors for LDL and growth factors [14,15], pigment granules [16] and integrins [17]. They also likely regulate non-vesicular trafficking by strengthening membrane contact sites between late endosomes and the ER [18].…”

“…They also likely regulate non-vesicular trafficking by strengthening membrane contact sites between late endosomes and the ER [18]. Consequently, TPCs are fast emerging as potential therapeutic targets in diverse disorders such as Parkinson's disease, fatty liver disease and cancer [12,14,17,19]. Moreover, TPCs have been identified as novel host factors for Ebola virus (EBOV) entry [20].…”