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DEPTOR is linked to a TORC1-p21 survival proliferation pathway in multiple myeloma cells

Yonghui Yang1, Carolyne Bardeleben1, Patrick Frost1

  • 1Department of Medicine, Hematology-Oncology, Greater Los Angeles VA Healthcare Center, Los Angeles, CA, USA ; UCLA School of Medicine, Greater Los Angeles VA Healthcare Center, Los Angeles, CA, USA.

Genes & Cancer
|January 9, 2015
PubMed

Insights

Gene silencing of DEPTOR, a multiple myeloma (MM) cell growth regulator, triggers cell death via the TORC1/p21 pathway. This mechanism involves p21 upregulation and is influenced by p21-targeting microRNAs.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Cell Biology

Background:

  • Multiple myeloma (MM) is a hematological malignancy characterized by uncontrolled plasma cell proliferation.
  • The mechanistic target of rapamycin (mTOR) pathway is a key regulator of cell growth and survival, and its inhibition is a therapeutic strategy in cancer.
  • DEPTOR (Dishevelled, Egl-10, and Pleckstrin homology domains-containing protein) is an endogenous inhibitor of mTOR signaling.

Purpose of the Study:

  • To elucidate the mechanism by which gene silencing of DEPTOR induces cytoreductive effects on multiple myeloma cells.
  • To investigate the role of the mTOR pathway, specifically TORC1 and AKT/SGK signaling, in DEPTOR knockdown-induced MM cell death.
  • To determine the involvement of p21, endoplasmic reticulum (ER) stress, and microRNAs (miRNAs) in the anti-MM effects of DEPTOR silencing.

Main Methods:

  • Gene silencing of DEPTOR using inducible short hairpin RNA (shRNA) in MM cell lines (e.g., 8226).
  • Assessment of mTOR pathway activation (TORC1, AKT/SGK), apoptosis, cell cycle arrest, senescence, and ER stress markers.
  • Evaluation of p21 expression, p53 dependence, and the role of p21 knockdown or overexpression of AKT activity.
  • In vivo studies using a murine xenograft model and analysis of p21-targeting miRNAs.

Main Results:

  • DEPTOR knockdown induced TORC1 activation, apoptosis, cell cycle arrest, and senescence in MM cells.
  • Cytotoxic effects were dependent on TORC1 activity but not AKT activity, and were independent of ER stress.
  • DEPTOR silencing led to p53-independent p21 upregulation, which was crucial for MM cell death.
  • DEPTOR knockdown in vivo resulted in anti-MM effects associated with p21 upregulation and decreased expression of p21-targeting miRNAs.

Conclusions:

  • DEPTOR gene silencing effectively inhibits multiple myeloma cell growth and survival through a TORC1/p21 signaling axis.
  • p21 induction, independent of p53 and ER stress, is a critical mediator of DEPTOR knockdown-induced cytotoxicity in MM.
  • p21-targeting miRNAs may play a regulatory role in the DEPTOR-mediated control of MM cell fate.
Keywords:
AKTDEPTORER stressMultiple MyelomamTORC1p21

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