Journal Article

Sonic Hedgehog promotes multiple drug resistance by regulation of drug transport

Chao, K S C, Ajani, J, Izzo, J G, Sims-Mourtada, J

2007

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing,Nature Publishing Group
• Subject: ABC transporter / ABC transporters / Apoptosis / ATP Binding Cassette Transporter, Sub-Family B / ATP Binding Cassette Transporter, Sub-Family G, Member 2 / ATP-Binding Cassette Transporters - genetics / ATP-Binding Cassette Transporters - metabolism / ATP-Binding Cassette, Sub-Family B, Member 1 - genetics / ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism / Biological and medical sciences / Biological Transport - genetics / Biological Transport - physiology / Cancer / Carrier proteins / Cell Biology / Cell Line, Tumor / Cell physiology / Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes / Cellular signal transduction / Chemoresistance / Chemotherapy / Drug resistance / Drug Resistance, Multiple / Drug Resistance, Neoplasm / Fundamental and applied biological sciences. Psychology / Gene expression / Genetics / Hedgehog protein / Hedgehog Proteins - chemistry / Hedgehog Proteins - genetics / Hedgehog Proteins - physiology / Human Genetics / Humans / Internal Medicine / Kinases / MDR1 protein / Medicine / Medicine & Public Health / Molecular and cellular biology / Multidrug resistance / Neoplasm Proteins - genetics / Neoplasm Proteins - metabolism / Oncology / P-Glycoprotein / Pharmaceutical Preparations - administration & dosage / Pharmaceutical Preparations - metabolism / Physiological aspects / Protein transport / Risk factors / RNA, Small Interfering - genetics / short-communication / Signal transduction / Signal Transduction - genetics / Signal Transduction - physiology / siRNA / Transfection