Hight Throughput Screening for inhibitors of the ABC transporter ABCB6

University Of Kansas Medical Center, Kansas City KS

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Abstract

DESCRIPTION (provided by applicant): ATP binding cassette transporters play important roles in biology and medicine. ABCB6 a member of the B subfamily of half transporter is increasingly recognized as a relevant physiological and therapeutic target. Based upon its normal operation as a transporter of coproporphyrinogen III, the final protoporphyrin precursor in the cytoplasm, ABCB6 regulates cellular porphyrin biosynthesis. ABCB6 expression is upregulated in many tumor cell lines and in liver tumors where it appears to promote cancer cell survival and hepatocellular carcinoma tumor growth and proliferation. ABCB6 gene is amplified in tumor cells that acquire resistant to chemotherapy drugs suggesting that it has a dominant effect in tumor cells and might play a role in the development of therapy related drug resistance. ABCB6 expression is induced under cell stress, including hypoxia, where it promotes cell survival. Thus ABCB6 expression could promote multiple survival strategies that are usually the hallmark of tumor development and progression. The long term goal of this project proposal is to develop a high throughput screening assay for the identification of regulators of ABCB6 expression that can be used to understand not only the significance and role of ABCB6 in tumor growth and proliferation and therapy related drug resistance but also its substrate specificity and the function of this transporter in normal physiology and disease pathology. PUBLIC HEALTH RELEVANCE: ABCB6 a member of the B subfamily of half transporter is increasingly recognized as a relevant physiological and therapeutic target. The long term goal of this project proposal is to develop a high throughput screening assay for the identification of regulators of ABCB6 expression that can be used to understand not only the significance and role of ABCB6 in tumor growth and proliferation and therapy related drug resistance but also its substrate specificity and the function of this transporter in normal physiology and disease pathology.