TY - JOUR
T1 - Low PRKAB2 Expression Is Associated with Poor Outcomes in Pediatric Adrenocortical Tumors, and Treatment with Rottlerin Increases the PRKAB2 Level and Inhibits Tumorigenic Aspects in the NCI-H295R Adrenocortical Cancer Cell Line
AU - Xavier, Alcides Euzebio Tavares
AU - Veronez, Luciana Chain
AU - Nagano, Luís Fernando Peinado
AU - Correa, Carolina Alves Pereira
AU - Baroni, Mirela
AU - Ramos, Milena Silva
AU - Queiroz, Rosane de Gomes de Paula
AU - Fernandes Molina, Carlos Augusto
AU - Yunes, José Andres
AU - Brandalise, Silvia Regina
AU - Antonini, Sonir Antonio Rauber
AU - Tone, Luiz Gonzaga
AU - Valera, Elvis Terci
AU - Scrideli, Carlos Alberto
N1 - Publisher Copyright:
© 2024 by the authors.
PY - 2024/3
Y1 - 2024/3
N2 - Pediatric adrenocortical tumors (ACTs) are rare, highly heterogeneous neoplasms with limited therapeutic options, making the investigation of new targets with potential therapeutic or prognostic purposes urgent. The PRKAB2 gene produces one of the subunits of the AMP-activated protein kinase (AMPK) complex and has been associated with cancer. However, little is known about the role AMPK plays in ACTs. We have evaluated how PRKAB2 is associated with clinical and biological characteristics in 63 pediatric patients with ACTs and conducted in vitro studies on the human NCI-H295R ACC cell line. An analysis of our cohort and the public ACC pediatric dataset GSE76019 showed that lower PRKAB2 expression was associated with relapse, death, metastasis, and lower event-free and overall survival rates. Multivariate analysis showed that PRKAB2 expression was an independent prognostic factor when associated with age, tumor weight and volume, and metastasis. In vitro tests on NCI-H295R cells demonstrated that Rottlerin, a drug that can activate AMPK, modulated several pathways in NCI-H295R cells, including AMPK/mTOR, Wnt/β-catenin, SKP2, HH, MAPK, NFKB, and TNF. Treatment with Rottlerin decreased cell proliferation and migration, clonogenic capacity, and steroid production. Together, these results suggest that PRKAB2 is a potential prognostic marker in pediatric ACTs, and that Rottlerin is promising for investigating drugs that can act against ACTs.
AB - Pediatric adrenocortical tumors (ACTs) are rare, highly heterogeneous neoplasms with limited therapeutic options, making the investigation of new targets with potential therapeutic or prognostic purposes urgent. The PRKAB2 gene produces one of the subunits of the AMP-activated protein kinase (AMPK) complex and has been associated with cancer. However, little is known about the role AMPK plays in ACTs. We have evaluated how PRKAB2 is associated with clinical and biological characteristics in 63 pediatric patients with ACTs and conducted in vitro studies on the human NCI-H295R ACC cell line. An analysis of our cohort and the public ACC pediatric dataset GSE76019 showed that lower PRKAB2 expression was associated with relapse, death, metastasis, and lower event-free and overall survival rates. Multivariate analysis showed that PRKAB2 expression was an independent prognostic factor when associated with age, tumor weight and volume, and metastasis. In vitro tests on NCI-H295R cells demonstrated that Rottlerin, a drug that can activate AMPK, modulated several pathways in NCI-H295R cells, including AMPK/mTOR, Wnt/β-catenin, SKP2, HH, MAPK, NFKB, and TNF. Treatment with Rottlerin decreased cell proliferation and migration, clonogenic capacity, and steroid production. Together, these results suggest that PRKAB2 is a potential prognostic marker in pediatric ACTs, and that Rottlerin is promising for investigating drugs that can act against ACTs.
KW - adrenocortical tumor
KW - AMPK
KW - biomarker
KW - PRKAB2
KW - Rottlerin
UR - http://www.scopus.com/inward/record.url?scp=85188731027&partnerID=8YFLogxK
U2 - 10.3390/cancers16061094
DO - 10.3390/cancers16061094
M3 - Article
AN - SCOPUS:85188731027
SN - 2072-6694
VL - 16
JO - Cancers
JF - Cancers
IS - 6
M1 - 1094
ER -