Nicotinic acid adenine dinucleotide phosphate (NAADP) induces intracellular Ca2+ release through the two-pore channel tpc1 in metastatic colorectal cancer cells

Pawan Faris, Giorgia Pellavio, Federica Ferulli, Francesca Di Nezza, Mudhir Shekha, Dmitry Lim, Marcello Maestri, Germano Guerra, Luigi Ambrosone, Paolo Pedrazzoli, Umberto Laforenza, Daniela Montagna, Francesco Moccia

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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 (InsP 3 )-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 InsP 3 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.

Original languageEnglish
Article number542
Issue number4
Publication statusPublished - Apr 1 2019



  • Cancer
  • Colorectal carcinoma
  • Lysosomal Ca signalling
  • Proliferation
  • TPC1

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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