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BMP4 reverses multidrug resistance through modulation of BCL-2 and GDNF in glioblastoma
Baohui Liu1, Qianxue Chen, Daofeng Tian
1Renmin Hospital, Wuhan University, 238 Jiefang Street, Wuhan 430060, Hubei, China.
Abstract:
Patients with glioblastoma are commonly treated with chemotherapy. But a significant proportion of patients develop disease progression after an initial response to chemotherapy. Presently, there is no standard of care for such patients. The bone morphogenetic protein 4 (BMP4) has been reported to play a tumor-suppressing role in glioblastoma, but its role in glioblastoma multidrug resistance (MDR) is not clear. We reported that BMP4 can reverse MDR of glioblastoma through the inhibition of B-cell lymphoma 2(BCL-2) and glial cell derived neurotrophic factor (GDNF). We showed that the expression level of BMP4 was lower in glioblastoma compared to normal brain tissue, and also showed that BMP4 expression decreased in multidrug resistance cell line U251/TMZ compared to U251 cells. Our research demonstrated that over-expression of BMP4 can reverse the multidrug resistance. BCL-2 and GDNF were inhibited when BMP4 was over-expressed, and this data were consistent with the negative relationship in human samples; analysis of 40 patient's glioblastoma and brain samples revealed a significant negative correlation between BMP4 and BCL-2, GDNF. When BCL-2 and GDNF were knocked down, the effect of BMP4 in regulating MDR was partially lost. This novel result showed, for the first time, that BMP4 can reverse MDR in glioblastoma, which involved negative inhibition of BCL-2 and GDNF.
Insights
Bone morphogenetic protein 4 (BMP4) reverses glioblastoma multidrug resistance (MDR) by inhibiting B-cell lymphoma 2 (BCL-2) and glial cell derived neurotrophic factor (GDNF). Lower BMP4 expression correlates with glioblastoma MDR, suggesting BMP4 as a potential therapeutic target.
Area of Science:
- Neuro-oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Glioblastoma chemotherapy often leads to disease progression due to multidrug resistance (MDR).
- A standard treatment for glioblastoma MDR is currently lacking.
- The tumor-suppressing role of bone morphogenetic protein 4 (BMP4) in glioblastoma is known, but its effect on MDR is unclear.
Purpose of the Study:
- To investigate the role of BMP4 in glioblastoma multidrug resistance (MDR).
- To elucidate the molecular mechanisms by which BMP4 influences glioblastoma MDR.
Main Methods:
- Compared BMP4 expression levels in glioblastoma tissues and cell lines (including a multidrug-resistant line).
- Overexpressed BMP4 in glioblastoma cells to assess its effect on drug resistance.
- Analyzed the expression of B-cell lymphoma 2 (BCL-2) and glial cell derived neurotrophic factor (GDNF) in relation to BMP4.
- Correlated BMP4, BCL-2, and GDNF expression in patient samples.
- Utilized gene knockdown techniques for BCL-2 and GDNF to validate BMP4's mechanism.
Main Results:
- BMP4 expression was significantly lower in glioblastoma tissues and MDR cell lines compared to normal tissues and sensitive cells.
- Overexpression of BMP4 reversed multidrug resistance in glioblastoma cells.
- BMP4 overexpression led to the inhibition of BCL-2 and GDNF.
- A significant negative correlation was observed between BMP4 and BCL-2/GDNF expression in patient samples.
- Knockdown of BCL-2 and GDNF partially abolished the MDR-reversing effect of BMP4.
Conclusions:
- BMP4 plays a crucial role in overcoming glioblastoma multidrug resistance.
- BMP4 reverses MDR by negatively inhibiting the expression of BCL-2 and GDNF.
- BMP4 represents a novel therapeutic target for overcoming chemotherapy resistance in glioblastoma.
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