TY - JOUR
T1 - A selective competitive inhibitor of aldehyde dehydrogenase 1A3 hinders cancer cell growth, invasiveness and stemness in vitro
AU - Gelardi, Edoardo L. M.
AU - Colombo, Giorgia
AU - Picarazzi, Francesca
AU - Ferraris, Davide M.
AU - Mangione, Andrea
AU - Petrarolo, Giovanni
AU - Aronica, Eleonora
AU - Rizzi, Menico
AU - Mori, Mattia
AU - la Motta, Concettina
AU - Garavaglia, Silvia
N1 - Funding Information: Funding: S.G. and D.M.F. acknowledges the University of Piemonte Orientale (grant Ricerca Ateneo FAR_2016 and FAR_2019) and ROCHE per la Ricerca 2017 for the financial support. Funding Information: S.G. and D.M.F. acknowledges the University of Piemonte Orientale (grant Ricerca Ateneo FAR_2016 and FAR_2019) and ROCHE per la Ricerca 2017 for the financial support. All the authors thank the ESRF for data collections at the beam lines ID30A. E.L.M.G., G.C. and S.G. acknowledge Cristina Travelli and Oliver B. Clarke for the help in the critique rereading of the paper. We acknowledge the HIS Mouse Facility of the Academic Medical Center, Amsterdam and the Bloemenhove Clinic (Heemstede, The Netherlands) for providing fetal tissues. Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/1/2
Y1 - 2021/1/2
N2 - Aldehyde dehydrogenase 1A3 (ALDH1A3) belongs to an enzymatic superfamily composed by 19 different isoforms, with a scavenger role, involved in the oxidation of a plethora of aldehydes to the respective carboxylic acids, through a NAD+‐dependent reaction. Previous clinical studies highlighted the high expression of ALDH1A3 in cancer stem cells (CSCs) correlated to a higher risk of cancer relapses, chemoresistance and a poor clinical outcome. We report on the structural, biochemical, and cellular characterization of NR6, a new selective ALDH1A3 inhibitor derived from an already published ALDH non‐selective inhibitor with cytotoxic activity on glioblastoma and colorectal cancer cells. Crystal structure, through X‐Ray analysis, showed that NR6 binds a non‐conserved tyrosine residue of ALDH1A3 which drives the selectivity towards this isoform, as supported by computational binding simulations. Moreover, NR6 shows anti‐metastatic activity in wound healing and invasion assays and induces the downregulation of cancer stem cell markers. Overall, our work confirms the role of ALDH1A3 as an important target in glioblastoma and colorectal cells and propose NR6 as a promising molecule for future preclinical studies.
AB - Aldehyde dehydrogenase 1A3 (ALDH1A3) belongs to an enzymatic superfamily composed by 19 different isoforms, with a scavenger role, involved in the oxidation of a plethora of aldehydes to the respective carboxylic acids, through a NAD+‐dependent reaction. Previous clinical studies highlighted the high expression of ALDH1A3 in cancer stem cells (CSCs) correlated to a higher risk of cancer relapses, chemoresistance and a poor clinical outcome. We report on the structural, biochemical, and cellular characterization of NR6, a new selective ALDH1A3 inhibitor derived from an already published ALDH non‐selective inhibitor with cytotoxic activity on glioblastoma and colorectal cancer cells. Crystal structure, through X‐Ray analysis, showed that NR6 binds a non‐conserved tyrosine residue of ALDH1A3 which drives the selectivity towards this isoform, as supported by computational binding simulations. Moreover, NR6 shows anti‐metastatic activity in wound healing and invasion assays and induces the downregulation of cancer stem cell markers. Overall, our work confirms the role of ALDH1A3 as an important target in glioblastoma and colorectal cells and propose NR6 as a promising molecule for future preclinical studies.
KW - Aldehyde dehydrogenases
KW - Biochemistry
KW - Cancer stem cells
KW - Cancer therapy
KW - Glioblastoma
KW - Structural biology
KW - Target validation
UR - http://www.scopus.com/inward/record.url?scp=85100103325&partnerID=8YFLogxK
U2 - https://doi.org/10.3390/cancers13020356
DO - https://doi.org/10.3390/cancers13020356
M3 - Article
C2 - 33478031
SN - 2072-6694
VL - 13
SP - 1
EP - 20
JO - Cancers
JF - Cancers
IS - 2
M1 - 356
ER -