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JNK initiates Beclin-1 dependent autophagic cell death against Akt activation

Chao Zeng1, Zhixuan Zhang2, Wei Luo3

  • 1Department of Gastroenterology, The Third People's Hospital of Chengdu, Chengdu, 610031, PR China.

Experimental Cell Research
|March 20, 2022
PubMed

Insights

ABT-199 triggers autophagic cell death in cancer cells lacking Bax and Bak proteins. This process involves the JNK-Akt-14-3-3 pathway and Beclin-1, suggesting potential applications for ABT-199 in apoptosis-resistant solid tumors.

Area of Science:

  • Cellular biology
  • Molecular oncology
  • Cancer research

Background:

  • ABT-199 (Venetoclax) is a selective BCL-2 inhibitor primarily investigated for hematological malignancies.
  • Its role in solid tumors, especially those with impaired apoptosis, remains less explored.
  • Understanding alternative cell death pathways induced by ABT-199 is crucial for expanding its therapeutic potential.

Purpose of the Study:

  • To investigate the mechanism of ABT-199-induced cell death in the absence of Bax and Bak.
  • To elucidate the role of autophagy in ABT-199 treatment in apoptosis-deficient cells.
  • To identify the signaling pathways mediating ABT-199's effects.

Main Methods:

  • Utilized Bax/Bak double knockout (KO) and knockdown (KD) cell models.
  • Analyzed ABT-199's effect on autophagy and cell death.
  • Investigated the involvement of Beclin-1, Akt, and JNK signaling pathways through phosphorylation and protein interaction studies.

Main Results:

  • ABT-199 induced Beclin-1-dependent autophagic cell death independently of Bax and Bak.
  • Inactivated Akt released Beclin-1 from 14-3-3 protein via altered Beclin-1 phosphorylation.
  • JNK activation antagonized Akt by phosphorylating 14-3-3, reducing its interaction with Beclin-1, thus activating autophagy.

Conclusions:

  • ABT-199 activates the JNK-Akt-14-3-3 signaling pathway to induce Beclin-1-dependent autophagic cell death in Bax/Bak deficient cells.
  • This mechanism highlights a novel route for cancer cell death.
  • Findings suggest ABT-199 could be a viable therapeutic option for apoptosis-deficient solid tumors like colon cancer.
Keywords:
ABT-199AktAutophagyBeclin-1Cell deathJNK

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