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Nicotinic acid adenine dinucleotide phosphate (NAADP) gates two-pore channels 1 and 2 (TPC1 and TPC2) to elicit endo-lysosomal (EL) Ca 2+ release. NAADP-induced EL Ca 2+ signals may be amplified by the endoplasmic reticulum (ER) through the Ca 2+ -induced Ca 2+ release mechanism (CICR). Herein, we aimed at assessing for the first time the role of EL Ca 2+ signaling in primary cultures of human metastatic colorectal carcinoma (mCRC) by exploiting Ca 2+ imaging and molecular biology techniques. The lysosomotropic agent, Gly-Phe β-naphthylamide (GPN), and nigericin, which dissipates the ΔpH which drives Ca 2+ refilling of acidic organelles, caused massive Ca 2+ release in the presence of a functional inositol-1,4,5-trisphosphate (InsP₃)-sensitive ER Ca 2+ store. Liposomal delivery of NAADP induced a transient Ca 2+ release that was reduced by GPN and NED-19, a selective TPC antagonist. Pharmacological and genetic manipulations revealed that the Ca 2+ response to NAADP was triggered by TPC1, the most expressed TPC isoform in mCRC cells, and required ER-embedded InsP₃ receptors. Finally, NED-19 and genetic silencing of TPC1 reduced fetal calf serum-induced Ca 2+ signals, proliferation, and extracellular signal-regulated kinase and Akt phoshorylation in mCRC cells. These data demonstrate that NAADP-gated TPC1 could be regarded as a novel target for alternative therapies to treat mCRC.

cancers

Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) Induces Intracellular Ca2+ Release through the Two-Pore Channel TPC1 in Metastatic Colorectal Cancer Cells