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The Aryl Hydrocarbon Receptor Undergoes Chaperone-Mediated Autophagy in Triple-Negative Breast Cancer Cells

Jinyun Chen1, Yujie Yang1, Wade A Russu1

  • 1Department of Pharmaceutics & Medicinal Chemistry, Thomas J. Long School of Pharmacy, University of the Pacific, Stockton, CA 95211, USA.

International Journal of Molecular Sciences
|February 10, 2021
PubMed

Insights

Triple-negative breast cancer cells degrade the aryl hydrocarbon receptor (AHR) via chaperone-mediated autophagy, a process distinct from its usual proteasomal degradation. This pathway involves specific triggers and interactions, offering new therapeutic targets.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cellular Degradation Pathways

Background:

  • The aryl hydrocarbon receptor (AHR) is a signaling molecule in breast cancer cells, influencing growth and estrogen receptor crosstalk.
  • AHR is typically degraded by the 26S proteasome after ligand activation.

Purpose of the Study:

  • To investigate the degradation mechanism of AHR in triple-negative breast cancer (TNBC) cells.
  • To identify specific triggers, inhibitors, and molecular players involved in AHR degradation in TNBC.

Main Methods:

  • Investigated AHR degradation in MDA-MB-468 (TNBC) and MCF-7, T47D, MDA-MB-361 (non-TNBC) cell lines.
  • Utilized chemical inducers (6-amino-nicotinamide, Q18), starvation, and specific inhibitors (progesterone receptor B, chloroquine, MG132).
  • Examined protein-protein interactions (AHR-HSC70, AHR-LAMP2A) and identified a KFERQ-like motif (NEKFF) in AHR.

Main Results:

  • AHR undergoes chaperone-mediated autophagy (CMA) in TNBC cells, distinct from proteasomal degradation.
  • CMA of AHR is triggered by specific compounds and starvation, and is cell-type specific to TNBC.
  • Progesterone receptor B inhibits AHR-CMA, while chloroquine reverses it; LAMP2A and HSC70 are essential, involving AHR's NEKFF motif.

Conclusions:

  • AHR degradation in TNBC cells occurs via CMA, a novel pathway dependent on LAMP2A and HSC70.
  • The NEKFF sequence in AHR acts as a CMA recognition motif, mediating its lysosomal degradation.
  • This distinct degradation mechanism in TNBC offers potential therapeutic targets for breast cancer treatment.
Keywords:
CMA motifLAMP2Aaryl hydrocarbon receptorchaperone-mediated autophagyprotein degradation

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