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Inositol Polyphosphate 4-Phosphatase Type II Is a Tumor Suppressor in Multiple Myeloma
Yafei Wang1, Lin Chen1,2, Qian Li1
1Department of Hematology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China.
Abstract:
Inositol polyphosphate-4-phosphatase type II (INPP4B) has been identified as a tumor suppressor, while little is known about its expression and function in multiple myeloma (MM). In this study, we evaluated the expression of INPP4B in 28 cases of newly diagnosed MM patients and 42 cases of extramedullary plasmacytoma (EMP) patients compared with normal plasma cells and found that low INPP4B expression was correlated with poor outcomes in MM patients. Moreover, expression of INPP4B in seven MM cell lines was all lower than that in normal plasma cells. In addition, loss of function of INPP4B promoted cell proliferation in MM cells; however, gain of function suppressed MM cells proliferation and arrested the cell cycle at G0/G1 phage. Meanwhile, knockdown of INPP4B enhanced resistance, but overexpression promoted sensitivity to bortezomib treatment in MM cells. Mechanistically, we found that INPP4B exerted its role via inhibiting the phosphorylation of Akt at lysine 473 but not threonine 308, which attenuated the activation of the PI3K/Akt/mammalian target of rapamycin (mTOR) signaling pathway. Therefore, we identified an inhibitory effect of INPP4B in MM, and our findings suggested that loss of INPP4B expression is a risk factor of aggressive MM.
Insights
Inositol polyphosphate-4-phosphatase type II (INPP4B) acts as a tumor suppressor in multiple myeloma (MM). Low INPP4B expression correlates with poor outcomes and aggressive disease, suggesting its potential as a therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Inositol polyphosphate-4-phosphatase type II (INPP4B) is recognized as a tumor suppressor.
- Its role and expression in multiple myeloma (MM) remain largely uncharacterized.
Purpose of the Study:
- To investigate the expression and functional significance of INPP4B in multiple myeloma.
- To elucidate the underlying mechanisms of INPP4B's action in MM.
Main Methods:
- Expression analysis of INPP4B in MM patient samples and cell lines.
- In vitro functional assays including loss-of-function and gain-of-function studies.
- Investigation of signaling pathways, specifically PI3K/Akt/mTOR, through Western blotting.
Main Results:
- Low INPP4B expression was observed in MM patients and cell lines, correlating with poor prognosis.
- Loss of INPP4B promoted MM cell proliferation, while its overexpression suppressed proliferation and induced G0/G1 cell cycle arrest.
- INPP4B modulated sensitivity to bortezomib treatment and inhibited Akt phosphorylation at Lysine 473, thereby attenuating PI3K/Akt/mTOR signaling.
Conclusions:
- INPP4B exhibits an inhibitory role in multiple myeloma.
- Reduced INPP4B expression is a significant risk factor for aggressive MM, highlighting its potential as a therapeutic target.
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