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Fludarabine resistance mediated by aminoglycoside-3′-phosphotransferase-IIa and the structurally related eukaryotic cAMP-dependent protein kinase

AuthorsSánchez-Carrera, Damaso; Bravo-Navas, Sara; Cabezón, Elena ; Arechaga, Ignacio ; Cabezas, Matilde; Yáñez, Lucrecia; Pipaón, Carlos
KeywordsPurine analogues
FANC proteins
DNA damage
Protein kinase A
Issue Date2017
PublisherFederation of American Societies for Experimental Biology
CitationFASEB Journal 31(7): 3007-3017 (2017)
AbstractWhile working with G418-resistant stably transfected cells, we realized the neomycin resistance (NeoR) gene, which encodes the aminoglycoside-3′-phosphotransferase-IIa [APH(3′)-IIa], also confers resistance to the nucleoside analog fludarabine. Fludarabine is a cytostatic drug widely used in the treatment of hematologic and solid tumors, as well as in the conditioning of patients before transplantation of hematopoietic progenitors. We present evidence that NeoR-transfected cells do not incorporate fludarabine, thus avoiding DNA damage caused by the drug, evidenced by a lack of FANCD2 monoubiquitination and impaired apoptosis. A screening of other nucleoside analogs revealed that APH(3′)-IIa only protects against ATP purine analogs. Moreover, APH(3′)-IIa ATPase activity is inhibited by fludarabine monophosphate, suggesting that APH(3′)-IIa blocks fludarabine incorporation into DNA by dephosphorylating its active fludarabine triphosphate form. Furthermore, overexpression of the catalytic subunit of the eukaryotic kinase PKA, which is structurally related to APHs, also provides resistance to fludarabine, anticipating its putative utility as a response marker to the drug. Our results preclude the use of Neo marker plasmids in the study of purine analogs and unveils a new resistance mechanism against these chemotherapeuticals.
Identifiersdoi: 10.1096/fj.201601245R
e-issn: 1530-6860
issn: 0892-6638
Appears in Collections:(IBBTEC) Artículos
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