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MAPK1/3 kinase-dependent ULK1 degradation attenuates mitophagy and promotes breast cancer bone metastasis

Rong Deng1, Hai-Liang Zhang1, Jun-Hao Huang1,2

  • 1State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China.

Autophagy
|November 20, 2020
PubMed

Insights

ULK1 deficiency impairs mitophagy, promoting breast cancer bone metastasis via NLRP3 inflammasome activation. Inhibiting the MAP2K/MEK-MAPK1/3 pathway restores mitophagy and reduces metastasis.

Area of Science:

  • Cell Biology
  • Cancer Biology
  • Molecular Oncology

Background:

  • Mitophagy, a selective form of autophagy, plays a complex role in cancer.
  • ULK1 (unc-51 like autophagy activating kinase 1) is crucial for autophagy and mitophagy, particularly under hypoxic conditions.

Purpose of the Study:

  • To investigate the role of ULK1 in breast cancer progression and bone metastasis under hypoxia.
  • To elucidate the molecular mechanisms linking ULK1 deficiency, mitophagy, and metastasis.

Main Methods:

  • Utilized ULK1 knockout breast cancer cells and hypoxia models.
  • Assessed mitophagy, mitochondrial reactive oxygen species (mtROS), NLRP3 inflammasome activation, and osteoclast differentiation.
  • Analyzed ULK1 phosphorylation, ubiquitination, and proteasomal degradation.
  • Correlated ULK1 and p-MAPK1/3 expression in human breast cancer tissues.
  • Tested the efficacy of the MAP2K/MEK inhibitor trametinib.

Main Results:

  • ULK1 deficiency in breast cancer cells under hypoxia led to impaired mitophagy and increased invasiveness.
  • Accumulation of damaged mitochondria and elevated mtROS activated the NLRP3 inflammasome, promoting osteoclast differentiation and bone metastasis.
  • ULK1 degradation was mediated by MAPK1/ERK2-MAPK3/ERK1 phosphorylation and BTRC-dependent ubiquitination.
  • Low ULK1 expression correlated with high p-MAPK1/3 in human breast cancer tissues.
  • Trametinib treatment restored mitophagy, inhibited NLRP3 inflammasome, and reduced bone metastasis.

Conclusions:

  • ULK1 deficiency-driven mitophagy defects promote breast cancer bone metastasis.
  • The MAP2K/MEK-MAPK1/3 pathway regulates ULK1 stability and mitophagy.
  • Targeting this pathway with inhibitors like trametinib shows therapeutic potential for breast cancers with low ULK1 levels.
Keywords:
Bone metastasisMAPK1/3 kinaseNLRP3 inflammasomeULK1breast cancermitophagy deficiency

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