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Protective autophagy induced by RBX1/ROC1 knockdown or CRL inactivation via modulating the DEPTOR-MTOR axis

Dongqin Yang1, Yongchao Zhao, Jie Liu

  • 1Department of Immunology, Shanghai Medical College, Fudan University, Shanghai, China.

Autophagy
|September 12, 2012
PubMed

Insights

RBX1, a key component of Cullin-RING E3 ligases, is overexpressed in liver cancer. Inhibiting RBX1 triggers cell senescence and autophagy, offering a potential therapeutic strategy for cancer treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • RBX1/ROC1 is a crucial subunit of Cullin-RING E3 ligases (CRL), regulating diverse cellular processes through substrate degradation.
  • RBX1 overexpression correlates with poor patient survival in hepatocellular carcinoma (HCC).

Purpose of the Study:

  • To investigate the role of RBX1 in liver cancer proliferation and identify potential therapeutic targets.
  • To explore the interplay between RBX1, senescence, and autophagy in cancer cells.

Main Methods:

  • siRNA-mediated knockdown of RBX1 in liver cancer cells (in vitro and in vivo).
  • Analysis of cell proliferation, senescence (CDKN1A/p21), autophagy, and apoptosis.
  • Observation of cancer cells treated with MLN4924, a CRL inhibitor.

Main Results:

  • RBX1 silencing inhibited HCC proliferation via CDKN1A/p21-dependent senescence.
  • RBX1 knockdown induced an autophagy response, partly due to DEPTOR accumulation.
  • Autophagy inhibition enhanced RBX1 knockdown's anti-proliferative effects by inducing apoptosis, suggesting autophagy acts as a survival mechanism.
  • Similar effects were observed in other cancer types upon CRL inhibition.

Conclusions:

  • RBX1-CRL is a promising anti-cancer drug target.
  • Combining RBX1-CRL inhibitors with autophagy inhibitors presents a novel therapeutic strategy for human cancers.

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