Inhibition of the Aryl Hydrocarbon Receptor - Polyamine Biosynthesis Axis Suppresses Multiple Myeloma and prostate cancer progression

Polyamine inhibition for cancer therapy is, conceptually, an attractive approach but has yet to meet success in the clinical setting. The aryl hydrocarbon receptor (AHR) is the central transcriptional regulator of xenobiotic response. Our study revealed that AHR also positively regulated intracellular polyamine production via direct transcriptional activation of two genes (ODC1 and AZIN1) involved in polyamine biosynthesis and control, respectively. In multiple myeloma patients, AHR levels inversely correlated with survival, suggesting that AHR inhibition may be beneficial for treatment of this disease .We identified clofazimine, an FDA-approved anti-leprosy drug, as a potent AHR antagonist and a suppressor of polyamine biosynthesis. Experiments in a transgenic model of multiple myeloma (Vk*Myc mice) and in immunocompromised mice bearing multiple myeloma cell xenografts, revealed high efficacy of clofazimine comparable to that of bortezomib, a first-in-class proteasome inhibitor used for treatment of multiple myeloma. This study identified a previously unrecognized regulatory axis between AHR and polyamine metabolism and discovered clofazimine as an inhibitor of AHR and a potentially clinically-relevant anti-multiple myeloma agent. RNA-seq: human multiple myeloma MM1S and human normal fibroblasts WI38 cells -/+ CLF 2-4uM for 24hrs; -/+ shAHR 18 samples total, 9 experimental conditions (each in duplicate): MM1S_pLKO_NT_2hrs ; MM1S_pLKO_NT_24hrs; MM1S_pLKO_CLF_2uM_24hrs; MM1S_shAHR2; MM1S_shAHR_3; WI38_pLKO_NT; WI38_pLKO_CLF_4uM; WI38_shAHR1; WI38_shAHR4