Related Experiment Videos
Loss of PTEN expression leading to high Akt activation in human multiple myelomas
1Laboratory of Cellular and Molecular Biology, National Cancer Institute, Bethesda, MD, USA.
Abstract:
Mouse plasma cell tumor (PCT) and human multiple myeloma (MM) are terminal B-cell malignancies sharing many similarities. Our recent work demonstrated that activation of the insulin-like growth factor receptor (IGF-IR)/insulin receptor substrate (IRS)/phosphatidylinositol 3' kinase (PI 3'K) pathway was evident in the tumor lines derived from both species. Although PI 3'K activity was higher in mouse tumor lines than that in human tumors, activation of Akt serine/threonine kinase was markedly lower in mouse lines. This discrepancy prompted us to test the status of PTEN tumor suppressor gene, as it has been shown to be a negative regulator of PI 3'K activity. Although all the mouse lines expressed intact PTEN, 2 of the 4 human lines (Delta47 and OPM2) possessing the highest Akt activity lost PTEN expression. Sequencing analysis demonstrated that the PTEN gene contains a deletion spacing from exon 3 to exon 5 or 6 in the Delta47 line and from exon 3 to 7 in the OPM2 line. Restoration of PTEN expression suppressed IGF-I-induced Akt activity, suggesting that loss of PTEN is responsible for uncontrolled Akt activity in these 2 lines. Despite the expression of PTEN with the concomitant low Akt activity in all mouse PCT lines, their p70S6K activities were generally higher than those in 3 human MM lines, arguing for specific negative regulation of Akt, but not p70S6K by PTEN. These results suggest that p70S6K and Akt may be differentially used by the plasma cell tumors derived from mice and humans, respectively.
Insights
Mouse plasma cell tumors and human multiple myeloma exhibit distinct pathway activations. Loss of the PTEN tumor suppressor gene in human multiple myeloma drives uncontrolled Akt activity, unlike in mouse models.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Mouse plasma cell tumors (PCT) and human multiple myeloma (MM) are related B-cell malignancies.
- The insulin-like growth factor receptor (IGF-IR)/insulin receptor substrate (IRS)/phosphatidylinositol 3' kinase (PI 3'K) pathway is activated in both PCT and MM.
- A discrepancy exists in Akt kinase activation between mouse and human tumors despite similar PI 3'K activity.
Purpose of the Study:
- To investigate the role of the PTEN tumor suppressor gene in explaining the observed differences in Akt activity between mouse PCT and human MM.
- To determine if PTEN loss is responsible for elevated Akt activity in specific human MM lines.
- To explore the differential regulation of Akt and p70S6K by PTEN in mouse and human plasma cell tumors.
Main Methods:
- Analysis of PTEN gene expression and sequencing in mouse PCT and human MM cell lines.
- Assessment of PI 3'K, Akt, and p70S6K kinase activities.
- Restoration of PTEN expression in human MM lines to observe effects on Akt activity.
Main Results:
- All mouse PCT lines expressed intact PTEN with lower Akt activity.
- Two human MM lines (Delta47 and OPM2) with high Akt activity showed loss of PTEN expression due to gene deletions.
- Restoring PTEN expression suppressed IGF-I-induced Akt activity in these human lines.
- Mouse PCT lines showed higher p70S6K activity than human MM lines, despite PTEN expression and low Akt activity, suggesting differential PTEN regulation.
Conclusions:
- Loss of PTEN is a key mechanism for uncontrolled Akt activation in specific human multiple myeloma cases.
- PTEN differentially regulates Akt and p70S6K, with Akt being specifically targeted in PTEN-deficient human MM.
- Mouse PCT and human MM utilize Akt and p70S6K pathways distinctively, highlighting species-specific oncogenic mechanisms.