Hedgehog signaling maintains chemoresistance in myeloid leukemic cells.
The development of resistance against chemotherapy remains one of the major challenges in the clinical management of leukemia. There is still limited insight into the molecular mechanisms that maintain the chemotherapy-resistant phenotype, despite the obvious clinical relevance that such knowledge would have. In this study, we show that the chemotherapy-resistant phenotype of myeloid leukemia cells correlates with activation of the Hedgehog (Hh) pathway, whereas in chemosensitive cells, such activation is less pronounced. Importantly, the overexpression of Hh pathway components induces chemoprotection and inhibition of the pathway reverts chemoresistance of Lucena-1 cells, apparently by interfering with P-glycoprotein-dependent drug resistance. Our data thus identify the Hh pathway as an essential component of multidrug resistance (MDR) myeloid leukemia and suggest that targeting the Hh pathway might be an interesting therapeutic avenue for overcoming MDR resistance in myeloid leukemia.
Queiroz
K C S
KC
Department of Biochemistry, Institute of Biology, University of Campinas, Campinas, São Paulo, Brazil. k.c.desouzaqueiroz@amc.uva.nl
Ruela-de-Sousa
R R
RR
Fuhler
G M
GM
Aberson
H L
HL
Ferreira
C V
CV
Peppelenbosch
M P
MP
Spek
C A
CA
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D053823:Hedgehog Proteins / Q000502:physiology*; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy*; D015398:Signal Transduction / Q000502:physiology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D053823:Hedgehog Proteins