Repositorio
Institucional

López-Muñoz, Rodrigo A.

Buelvas, Neudo

Ugarte-Vio, Isidora

Asencio-Leal, Laura

Munoz-Uribe, Matias

Martin-Martin, Antonia

Rojas-Fernandez, Alejandro

Jara, Jose A.

Tapia, Julio C.

Arias, Maria Elena

Indomethacin Induces Spermidine/Spermine-N1-Acetyltransferase-1 via the Nucleolin-CDK1 Axis and Synergizes with the Polyamine Oxidase Inhibitor Methoctramine in Lung Cancer Cells

MDPI

BIOMOLECULES

en

Indomethacin is a non-selective NSAID used against pain and inflammation. Although cyclooxygenase (COX) inhibition is considered indomethacin's primary action mechanism, COX-independent ways are associated with beneficial effects in cancer. In colon cancer cells, the activation of the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is related to the increase in spermidine/spermine-N-1-acetyltransferase-1 (SSAT-1), a key enzyme for polyamine degradation, and related to cell cycle arrest. Indomethacin increases the SSAT-1 levels in lung cancer cells, however, the mechanism relying on the SSAT-1 increase is unclear. Thus, we asked for the influence of the PPAR-gamma on the SSAT-1 expression in two lung cancer cell lines: H1299 and A549. We found that the inhibition of PPAR-gamma with GW9662 did not revert the increase in SSAT-1 induced by indomethacin. Because the mRNA of SSAT-1 suffers a pre-translation retention step by nucleolin, a nucleolar protein, we explored the relationship between indomethacin and the upstream translation regulators of SSAT-1. We found that indomethacin decreases the nucleolin levels and the cyclin-dependent kinase 1 (CDK1) levels, which phosphorylates nucleolin in mitosis. Overexpression of nucleolin partially reverts the effect of indomethacin over cell viability and SSAT-1 levels. On the other hand, Casein Kinase, known for phosphorylating nucleolin during interphase, is not modified by indomethacin. SSAT-1 exerts its antiproliferative effect by acetylating polyamines, a process reverted by the polyamine oxidase (PAOX). Recently, methoctramine was described as the most specific inhibitor of PAOX. Thus, we asked if methoctramine could increase the effect of indomethacin. We found that, when combined, indomethacin and methoctramine have a synergistic effect against NSCLC cells in vitro. These results suggest that indomethacin increases the SSAT-1 levels by reducing the CDK1-nucleolin regulatory axis, and the PAOX inhibition with methoctramine could improve the antiproliferative effect of indomethacin.

2023

artículo original

10.3390/biom13091383

PDF

polyamines

cancer

indomethacin

non-steroidal anti-inflammatory drugs

Bioquímica y biología molecular

poliaminas

cáncer

indometacina

fármacos anti-inflamatorios no esteroideos

artículo original

versión publicada

CC BY 4.0

CC BY 4.0

acceso abierto

acceso abierto

WOS:001075836000001

verde# dorado

Bioquímica y biología molecular

ANID-FONDECYT 1201378

ANID-FONDECYT 1200427

ANID-FONDEQUIP EQM180037

ANID-FONDECYT 1220353

ANID FONDECYT 1201378

ANID FONDECYT 1200427

ANID FONDEQUIP EQM180037

ANID FONDECYT 1220353