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Sh3glb1/Bif-1 and mitophagy: acquisition of apoptosis resistance during Myc-driven lymphomagenesis

Yoshinori Takahashi1, Megan M Young, Jacob M Serfass

  • 1Department of Pharmacology; Penn State Hershey Cancer Institute; Penn State College of Medicine; Hershey, PA USA.

Autophagy
|May 18, 2013
PubMed

Insights

SH3GLB1/Bif-1 acts as a tumor suppressor by regulating mitophagy, preventing apoptosis resistance and malignant transformation in Myc-driven lymphomas. Its loss impairs mitochondrial clearance, promoting cancer development.

Area of Science:

  • Cancer Biology
  • Cellular Biology
  • Molecular Oncology

Background:

  • Apoptosis evasion is a hallmark of cancer, enabling cell survival under metabolic stress.
  • SH3GLB1/Bif-1 has been identified as a tumor suppressor in Myc-driven lymphomagenesis.
  • SH3GLB1 regulates autophagy and membrane trafficking, crucial processes in cellular homeostasis.

Purpose of the Study:

  • To investigate the role of SH3GLB1/Bif-1 in preventing apoptosis resistance and malignant transformation.
  • To elucidate the mechanism by which SH3GLB1/Bif-1 regulates mitophagy and its impact on tumorigenesis.
  • To understand the interplay between SH3GLB1/Bif-1, autophagy, and mitochondrial quality control in cancer.

Main Methods:

  • Analysis of SH3GLB1 haploinsufficiency in Myc-driven lymphomagenesis.
  • Investigating SH3GLB1's interaction with BECN1/UVRAG and regulation of ATG9A trafficking.
  • Assessing mitophagy in SH3GLB1-deficient mouse embryonic fibroblasts (MEFs) treated with CCCP.
  • Examining autophagosome formation and mitochondrial mass in SH3GLB1-deficient cells.

Main Results:

  • SH3GLB1 haploinsufficiency enhances chromosomal instability and upregulates anti-apoptotic proteins (MCL1, BCL2L1).
  • Loss of SH3GLB1 increases mitochondrial mass and suppresses mitophagy in PARK2-expressing MEFs.
  • SH3GLB1-deficient cells accumulate ER-associated immature autophagosome-like structures upon CCCP treatment.
  • SH3GLB1 deficiency promotes oncogene-driven tumorigenesis by impairing mitochondrial clearance.

Conclusions:

  • SH3GLB1/Bif-1 functions as a haploinsufficient tumor suppressor by maintaining mitophagy and preventing apoptosis resistance.
  • SH3GLB1, as part of the PIK3C3CII complex, regulates ATG9A trafficking for autophagosome formation at damaged mitochondria.
  • Dysregulation of SH3GLB1-mediated mitophagy contributes to Myc-driven lymphomagenesis and cancer progression.
Keywords:
DNA damageMCL1MYCSH3GLB1/Bif-1apoptosisautophagychromosome instabilitylymphomamalignant transformationmitophagy

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