Hedgehog signaling maintains chemoresistance in myeloid leukemic cells

• Published in: Oncogene Vol. 29; no. 48; pp. 6314 - 6322
• Main Authors: Queiroz, K C S, Ruela-de-Sousa, R R, Fuhler, G M, Aberson, H L, Ferreira, C V, Peppelenbosch, M P, Spek, C A
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02.12.2010; Nature Publishing Group
• Subjects: 631/80/86; 692/699/67/1059/2326; 692/699/67/1990/283; Apoptosis; ATP-Binding Cassette, Sub-Family B, Member 1 - analysis; Biological and medical sciences; Cancer cells; Cell activation; Cell Biology; Cell Line, Tumor; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cellular signal transduction; Chemoprotection; Chemoresistance; Chemotherapy; Drug resistance; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug therapy; Fundamental and applied biological sciences. Psychology; Hedgehog protein; Hedgehog Proteins - physiology; Hematologic and hematopoietic diseases; Human Genetics; Humans; Internal Medicine; Kinases; Leukemia; Leukemia, Myeloid - drug therapy; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Medicine; Medicine & Public Health; Molecular and cellular biology; Molecular biology; Molecular modelling; Multidrug resistance; Multidrug resistant organisms; Myeloid leukemia; Oncology; original-article; P-Glycoprotein; Phenotypes; Physiological aspects; Signal transduction; Signal Transduction - physiology; Netherlands; P-glycoprotein; multidrug resistance; leukemia; Hedgehog; Leukemia; Multiple resistance; P Glycoprotein; Malignant hemopathy; Carcinogenesis; Myeloid cell; Cell signaling; Cancer
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2010.375

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.