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

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

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
JournalCancers
Volume11
Issue number4
DOIs
Publication statusPublished - Apr 1 2019

Fingerprint

Colorectal Neoplasms
Endoplasmic Reticulum
Nigericin
Inositol 1,4,5-Trisphosphate
Extracellular Signal-Regulated MAP Kinases
Complementary Therapies
Organelles
Molecular Biology
Protein Isoforms
NAADP
Pharmacology
Serum
glycylphenylalanine 2-naphthylamide
1-(3-((4-(2-fluorophenyl)piperazin-1-yl)methyl)-4-methoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido(3,4-b)indole-3-carboxylic acid

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Nicotinic acid adenine dinucleotide phosphate (NAADP) induces intracellular Ca2+ release through the two-pore channel tpc1 in metastatic colorectal cancer cells. / Faris, Pawan; Pellavio, Giorgia; Ferulli, Federica; Di Nezza, Francesca; Shekha, Mudhir; Lim, Dmitry; Maestri, Marcello; Guerra, Germano; Ambrosone, Luigi; Pedrazzoli, Paolo; Laforenza, Umberto; Montagna, Daniela; Moccia, Francesco.

In: Cancers, Vol. 11, No. 4, 542, 01.04.2019.

Research output: Contribution to journalArticle

Faris, Pawan ; Pellavio, Giorgia ; Ferulli, Federica ; Di Nezza, Francesca ; Shekha, Mudhir ; Lim, Dmitry ; Maestri, Marcello ; Guerra, Germano ; Ambrosone, Luigi ; Pedrazzoli, Paolo ; Laforenza, Umberto ; Montagna, Daniela ; Moccia, Francesco. / Nicotinic acid adenine dinucleotide phosphate (NAADP) induces intracellular Ca2+ release through the two-pore channel tpc1 in metastatic colorectal cancer cells. In: Cancers. 2019 ; Vol. 11, No. 4.
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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) 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.",
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AU - Pellavio, Giorgia

AU - Ferulli, Federica

AU - Di Nezza, Francesca

AU - Shekha, Mudhir

AU - Lim, Dmitry

AU - Maestri, Marcello

AU - Guerra, Germano

AU - Ambrosone, Luigi

AU - Pedrazzoli, Paolo

AU - Laforenza, Umberto

AU - Montagna, Daniela

AU - Moccia, Francesco

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N2 - 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.

AB - 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.

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