PHLPP Sensitizes Multiple Myeloma Cells to Bortezomib Through Regulating LAMP2
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Updated: Dec 29, 2025
An Organotypic High Throughput System for Characterization of Drug Sensitivity of Primary Multiple Myeloma Cells
Published on: July 15, 2015
Xiao Liu1, Chengyuan Li1, Yunfeng Fu1
1Department of Hematology, The Third Xiangya Hospital of Central South University, Changsha 410013, People's Republic of China.
Introduction:
Treatment of bortezomib (BTZ) improves the clinical outcomes of patients with multiple myeloma (MM). However, primary resistance and acquired resistance to BTZ frequently develop in patients with MM. PH domain leucine-rich repeat protein phosphatase (PHLPP) plays an important role in chemoresistance in a number of cancers. However, the role of PHLPP on MM remains unclear. In this study, we investigated the role of PHLPP in BTZ-resistant MM cells.
Methods:
BrdU assays, immunoprecipitation, flow cytometry analyses, and immunofluorescence assays were performed.
Results:
PHLPP and lysosome-associated membrane protein 2 (LAMP2) levels were downregulated in BTZ-resistant MM cells compared with BTZ-sensitive MM cells, accompanied by inactivation of autophagy pathway evaluated by a reduction in Beclin1, Atg5 and LC3B and increase in p62. Gain- and loss-of-function experiments revealed that PHLPP partially re-sensitized MM cells to BTZ. In addition, PHLPP overexpression increased whereas PHLPP knockdown reduced LAMP2 expression, subsequently regulating the autophagy pathway in MM cells. Further findings demonstrated that LAMP2 knockdown reversed PHLPP-mediated cell apoptosis and autophagy activation in MM cells.
Conclusion:
This study demonstrated that PHLPP is a potential strategy for overcoming BTZ resistance in patients with MM.
Insights
PH domain leucine-rich repeat protein phosphatase (PHLPP) is downregulated in bortezomib-resistant multiple myeloma (MM). Restoring PHLPP re-sensitizes MM cells to bortezomib by regulating autophagy and lysosome-associated membrane protein 2 (LAMP2).
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Bortezomib (BTZ) is a key treatment for multiple myeloma (MM), but resistance is a significant clinical challenge.
- PH domain leucine-rich repeat protein phosphatase (PHLPP) is implicated in chemoresistance in various cancers, but its role in MM is not well understood.
Purpose of the Study:
- To investigate the role of PHLPP in bortezomib-resistant multiple myeloma (MM) cells.
- To determine if PHLPP can overcome resistance to bortezomib in MM.
Main Methods:
- Cell viability assays (BrdU)
- Immunoprecipitation
- Flow cytometry
- Immunofluorescence assays
- Gain- and loss-of-function experiments
Main Results:
- PHLPP and lysosome-associated membrane protein 2 (LAMP2) levels were decreased in BTZ-resistant MM cells.
- PHLPP overexpression partially re-sensitized MM cells to BTZ and modulated autophagy.
- PHLPP regulated LAMP2 expression, which in turn influenced the autophagy pathway in MM cells.
- LAMP2 knockdown counteracted the effects of PHLPP on MM cell apoptosis and autophagy.
Conclusions:
- PHLPP plays a crucial role in modulating BTZ sensitivity in MM.
- PHLPP represents a potential therapeutic strategy to overcome bortezomib resistance in multiple myeloma patients.
