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

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.

The aryl hydrocarbon receptor repressor – More than a simple feedback inhibitor of AhR signaling: Clues for its role in inflammation and cancer

“…This mechanism supports recent findings showing that promotion of certain blood cancers (e.g. human multiple myeloma and anaplastic large cell lymphoma) rely on ARNT by antagonizing RelB and p53-dependent cell-cycle arrest and apoptosis (121). Expression of RelB was also shown to be critical for survival of Hodgkin lymphoma (122).…”

Paclitaxel-mediated human aryl hydrocarbon receptor mRNA translation by an internal ribosomal entry site-dependent mechanism

“…For instance, the IRES activity of TNF receptor-associated factor 1 (TRAF1) is simulated in leukemic cells treated with vincristine, the 5'-UTR of human sensitivity to nitrogen mustard (hSNM1) upregulates protein expression in HT-1080 cells during mitosis, and several apoptosis-inducing agents induce the IRES activity of cellular inhibitor of apoptosis protein 1 (c-IAP1) in 293T cells (42)(43)(44). Furthermore, previous studies have demonstrated that AHR nuclear translocator (ARNT isoform 1) impairs chemo-resistance and survival to cancer cells (45). Thus, the increasing concentration of chemotherapeutic drug PTX was used to treat A2780, MB231, Bel7402 and SW620 cell lines.…”

Mechanisms underlying the antiproliferative effects of a series of quinoxaline-derived chalcones

“…The downregulation of arnt , cdh2 , foxc2 , polb , and the overexpression of e2f4 and pinx, can help to explain the expressive pro-apoptotic effects exhibited by N9 in our study. Indeed, these genes are able to modulate the survival rates of various tumor cell lines 36 – 40 . Most of them have also been involved in cell migration, invasiveness, metastasis and angiogenesis 37 , 39 , 41 , and their regulation likely contributes with the tumor control.…”

“…The compounds N15 (R = 3′,4′,5′-triOCH 3 ), N16 (R = 3′-OCH 3 , 4′-OH), N17 (R = 2′,4′,5′-triOCH 3 ), N18 (R = 3′,5′-diOCH 3 ), N19 (R = 2-OCH 3 ), N20 (R = 3′,5′-diOCH 3 , 4′-OH), N23 (R = 3′-OCH 3 ) and N36 (R = 2′,3′,4′-triOCH 3 ) were described by Winter et al . (2014) 36 . The compounds N24 (R = 4-imidazol), N33 (R = 4-CN), N34 (R = 3-CN) and N37 (R = 4-F) are new chalcones.…”