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Cancers 2019, 11(4), 542; https://doi.org/10.3390/cancers11040542

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

1
Laboratory of General Physiology, Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, 27100 Pavia, Italy
2
Research Centre, Salahaddin University-Erbil, 44001 Erbil, Kurdistan-Region of Iraq, Iraq
3
Human Physiology Unit, via Forlanini 6, Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy
4
Laboratory of Immunology Transplantation, Foundation IRCCS Policlinico San Matteo, 27100 Pavia, Italy
5
Department of Medicine and Health Sciences “Vincenzo Tiberio”, University of Molise, 86100 Campobasso, Italy
6
Department of Pathological Analysis, College of Science, Knowledge University, 074016 Erbil, Kurdistan-Region of Iraq, Iraq
7
Department of Pharmaceutical Sciences, Università del Piemonte Orientale, 28100 Novara, Italy
8
Unit of General Surgery, Foundation IRCCS Policlinico San Matteo, 27100 Pavia, Italy
9
Department of Sciences Clinic-Surgical, Diagnostic and Pediatric, University of Pavia, 27100 Pavia, Italy
10
Medical Oncology, oundation IRCCS Policlinico San Matteo, 27100 Pavia, Italy
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Received: 2 April 2019 / Accepted: 9 April 2019 / Published: 15 April 2019
(This article belongs to the Special Issue Ion Channels in Cancer)
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Abstract

Nicotinic acid adenine dinucleotide phosphate (NAADP) gates two-pore channels 1 and 2 (TPC1 and TPC2) to elicit endo-lysosomal (EL) Ca2+ release. NAADP-induced EL Ca2+ signals may be amplified by the endoplasmic reticulum (ER) through the Ca2+-induced Ca2+ release mechanism (CICR). Herein, we aimed at assessing for the first time the role of EL Ca2+ signaling in primary cultures of human metastatic colorectal carcinoma (mCRC) by exploiting Ca2+ imaging and molecular biology techniques. The lysosomotropic agent, Gly-Phe β-naphthylamide (GPN), and nigericin, which dissipates the ΔpH which drives Ca2+ refilling of acidic organelles, caused massive Ca2+ release in the presence of a functional inositol-1,4,5-trisphosphate (InsP3)-sensitive ER Ca2+ store. Liposomal delivery of NAADP induced a transient Ca2+ release that was reduced by GPN and NED-19, a selective TPC antagonist. Pharmacological and genetic manipulations revealed that the Ca2+ 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 Ca2+ 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. View Full-Text
Keywords: NAADP; TPC1; lysosomal Ca2+ signalling; cancer; colorectal carcinoma; proliferation NAADP; TPC1; lysosomal Ca2+ signalling; cancer; colorectal carcinoma; proliferation
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Faris, P.; Pellavio, G.; Ferulli, F.; Di Nezza, F.; Shekha, M.; Lim, D.; Maestri, M.; Guerra, G.; Ambrosone, L.; Pedrazzoli, P.; Laforenza, U.; Montagna, D.; Moccia, F. Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) Induces Intracellular Ca2+ Release through the Two-Pore Channel TPC1 in Metastatic Colorectal Cancer Cells. Cancers 2019, 11, 542.

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