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Deptor transcriptionally regulates endoplasmic reticulum homeostasis in multiple myeloma cells
Valeria Catena1, Tiziana Bruno1, Francesca De Nicola1
1SAFU, Department of Research, Advanced Diagnostics, and Technological Innovation, Translational Research Area, Regina Elena National Cancer Institute, 00144, Rome, Italy.
Abstract:
Multiple myeloma (MM) is a malignant disorder of plasma cells characterized by active production and secretion of monoclonal immunoglobulins (IgG), thus rendering cells prone to endoplasmic reticulum (ER) stress. For this reason, MM cell survival requires to maintain ER homeostasis at basal levels. Deptor is an mTOR binding protein, belonging to the mTORC1 and mTORC2 complexes. It was reported that Deptor is overexpressed in MM cells where it inhibits mTOR kinase activity and promotes cell survival by activating Akt signaling. Here we identify Deptor as a nuclear protein, able to bind DNA and regulate transcription in MM cells. In particular, we found that Deptor plays an important role in the maintenance of the ER network, sustaining the expression of several genes involved in this pathway. In agreement with this, Deptor depletion induces ER stress and synergizes the effect of the proteasome inhibitor bortezomib (Bz) in MM cells. These findings provide important new insights in the ER stress control in MM cells.
Insights
Deptor, a protein overexpressed in multiple myeloma (MM), acts as a nuclear factor regulating endoplasmic reticulum (ER) homeostasis. Its depletion exacerbates ER stress and enhances bortezomib treatment efficacy in MM cells.
Area of Science:
- Oncology
- Molecular Biology
- Cellular Biology
Background:
- Multiple myeloma (MM) involves malignant plasma cells with high immunoglobulin production, leading to endoplasmic reticulum (ER) stress.
- Deptor, an mTOR-binding protein, is overexpressed in MM, inhibiting mTOR kinase and promoting survival via Akt signaling.
Purpose of the Study:
- To investigate the role of Deptor in multiple myeloma cell survival and ER homeostasis.
- To identify Deptor as a nuclear protein involved in regulating gene transcription related to ER function.
Main Methods:
- Identification of Deptor's subcellular localization (nuclear).
- Assessment of Deptor's DNA-binding and transcriptional regulatory capabilities.
- Analysis of Deptor's role in maintaining ER network and gene expression.
- Evaluation of Deptor depletion effects on ER stress and bortezomib sensitivity.
Main Results:
- Deptor is identified as a nuclear protein that binds DNA and regulates transcription in MM cells.
- Deptor is crucial for maintaining the ER network by sustaining the expression of key ER-related genes.
- Deptor depletion induces significant ER stress in MM cells.
- Depletion of Deptor synergizes with bortezomib, enhancing its anti-myeloma effect.
Conclusions:
- Deptor plays a critical role in maintaining ER homeostasis in multiple myeloma cells.
- Targeting Deptor may represent a novel therapeutic strategy to overcome bortezomib resistance in MM.
- These findings offer new insights into ER stress control mechanisms in multiple myeloma.
