Aryl hydrocarbon receptor nuclear translocator (ARNT) isoforms control lymphoid cancer cell proliferation through differentially regulating tumor suppressor p53 activity

Abstract

// Kacie A. Gardella 2,* , Israel Muro 1,* , Gloria Fang 1 , Krishnakali Sarkar 2 , Omayra Mendez 2 and Casey W. Wright 1,2 1 Division of Pharmacology and Toxicology, and the Center for Molecular and Cellular Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX, USA 2 Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX, USA * These authors have contributed equally to this work Correspondence to: Casey W. Wright, email: // Keywords : alternative splicing, ARNT, RelB, p53, lymphoid malignancies Received : September 22, 2015 Accepted : January 22, 2016 Published : February 20, 2016 Abstract The aryl hydrocarbon receptor nuclear translocator (ARNT) is involved in xenobiotic and hypoxic responses, and we previously showed that ARNT also regulates nuclear factor-κB (NF-κB) signaling by altering the DNA binding activity of the RelB subunit. However, our initial study of ARNT-mediated RelB modulation was based on simultaneous suppression of the two ARNT isoforms, isoform 1 and 3, and precluded the examination of their individual functions. We find here that while normal lymphocytes harbor equal levels of isoform 1 and 3, lymphoid malignancies exhibit a shift to higher levels of ARNT isoform 1. These elevated levels of ARNT isoform 1 are critical to the proliferation of these cancerous cells, as suppression of isoform 1 in a human multiple myeloma (MM) cell line, and an anaplastic large cell lymphoma (ALCL) cell line, triggered S-phase cell cycle arrest, spontaneous apoptosis, and sensitized cells to doxorubicin treatment. Furthermore, co-suppression of RelB or p53 with ARNT isoform 1 prevented cell cycle arrest and blocked doxorubicin induced apoptosis. Together our findings reveal that certain blood cancers rely on ARNT isoform 1 to potentiate proliferation by antagonizing RelB and p53-dependent cell cycle arrest and apoptosis. Significantly, our results identify ARNT isoform 1 as a potential target for anticancer therapies.