Sonic Hedgehog promotes multiple drug resistance by regulation of drug transport.
A major obstacle to successful chemotherapy is intrinsic or acquired multi-drug resistance (MDR). The most common cause of MDR involves increased drug efflux from cancer cells mediated by members of the ATP-binding cassette (ABC) transporter family. The regulation of ABC transporters in the context of cancer is poorly understood, and clinical efforts to inhibit their function have not been fruitful. Constitutive activation of the Hedgehog (Hh) pathway has been shown to contribute to the growth and maintenance of various cancers. Here, we show that inhibition of Hh signaling increases the response of cancer cells to multiple structurally unrelated chemotherapies. We further show that Hh pathway activation induces chemoresistance in part by increasing drug efflux in an ABC transporter-dependent manner. We found that Hh signaling regulates the expression of the ABC transporter proteins multi-drug resistance protein-1 (MDR1, ABCB1, P-glycoprotein) and (BCRP, ABCG2), and that targeted knockdown of MDR1 and BCRP expression by small interfering RNA partially reverses Hh-induced chemoresistance. These results suggest that the Hh pathway may be a target to overcome MDR and increase chemotherapeutic response.
Sims-Mourtada
J
J
Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Izzo
J G
JG
Ajani
J
J
Chao
K S C
KS
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D001692:Biological Transport / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D053823:Hedgehog Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D014162:Transfection
C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D053823:Hedgehog Proteins; D009363:Neoplasm Proteins; D004364:Pharmaceutical Preparations; D034741:RNA, Small Interfering; C509239:SHH protein, human