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Aryl hydrocarbon receptor nuclear translocator (ARNT) isoforms control lymphoid cancer cell proliferation through

Kacie A Gardella1, Israel Muro2, Gloria Fang2

  • 1Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX, USA.

Oncotarget
|February 25, 2016
PubMed

Insights

Certain blood cancers overexpress aryl hydrocarbon receptor nuclear translocator (ARNT) isoform 1, driving proliferation. Suppressing ARNT isoform 1 halts cancer growth and increases sensitivity to chemotherapy.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Cell Signaling

Background:

  • The aryl hydrocarbon receptor nuclear translocator (ARNT) regulates xenobiotic and hypoxic responses.
  • ARNT modulates nuclear factor-κB (NF-κB) signaling via the RelB subunit.
  • Previous studies could not differentiate the roles of ARNT isoforms 1 and 3.

Purpose of the Study:

  • To investigate the distinct roles of ARNT isoform 1 and 3 in lymphoid malignancies.
  • To determine the impact of ARNT isoform 1 on cancer cell proliferation and survival.
  • To explore ARNT isoform 1 as a potential therapeutic target in blood cancers.

Main Methods:

  • Comparative analysis of ARNT isoform levels in normal lymphocytes versus lymphoid malignancies.
  • Functional studies involving ARNT isoform 1 suppression in multiple myeloma (MM) and anaplastic large cell lymphoma (ALCL) cell lines.
  • Assessment of cell cycle progression, apoptosis, and drug sensitivity following ARNT isoform 1 manipulation.
  • Co-suppression experiments with RelB or p53 to elucidate ARNT isoform 1's mechanism of action.

Main Results:

  • Lymphoid malignancies show elevated ARNT isoform 1 levels compared to normal lymphocytes.
  • Suppression of ARNT isoform 1 induced S-phase cell cycle arrest and apoptosis in MM and ALCL cells.
  • ARNT isoform 1 suppression sensitized cancer cells to doxorubicin treatment.
  • Co-suppression of RelB or p53 with ARNT isoform 1 abrogated cell cycle arrest and doxorubicin-induced apoptosis.

Conclusions:

  • Elevated ARNT isoform 1 is crucial for the proliferation of certain blood cancers.
  • ARNT isoform 1 promotes cancer cell survival by antagonizing RelB and p53-dependent pathways.
  • ARNT isoform 1 represents a promising therapeutic target for treating specific lymphoid malignancies.
Keywords:
ARNTRelBalternative splicinglymphoid malignanciesp53

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