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Published on: January 7, 2019
NDUFA4L2 promotes glioblastoma progression, is associated with poor survival, and can be effectively targeted by
Zheng Chen1,2, Xiangyu Wei1,2, Xueyi Wang1,2
1Department of Neurosurgery, XinHua Hospital, Shanghai JiaoTong University School of Medicine, 1665 KongJiang Rd, 200092, Shanghai, China.
Abstract:
NADH dehydrogenase [ubiquinone] 1 alpha subcomplex, 4-like 2 (NDUFA4L2) is a subunit of Complex I of the mitochondrial respiratory chain, which is important in metabolic reprogramming and oxidative stress in multiple cancers. However, the biological role and molecular regulation of NDUFA4L2 in glioblastoma (GBM) are poorly understood. Here, we found that NDUFA4L2 was significantly upregulated in GBM; the elevated levels were correlated with reduced patient survival. Gene knockdown of NDUFA4L2 inhibited tumor cell proliferation and enhanced apoptosis, while tumor cells initiated protective mitophagy in vitro and in vivo. We used lentivirus to reduce expression levels of NDUFA4L2 protein in GBM cells exposed to mitophagy blockers, which led to a significant enhancement of tumor cell apoptosis in vitro and inhibited the development of xenografted tumors in vivo. In contrast to other tumor types, NDUFA4L2 expression in GBM may not be directly regulated by hypoxia-inducible factor (HIF)-1α, because HIF-1α inhibitors failed to inhibit NDUFA4L2 in GBM. Apatinib was able to effectively target NDUFA4L2 in GBM, presenting an alternative to the use of lentiviruses, which currently cannot be used in humans. Taken together, our data suggest the use of NDUFA4L2 as a potential therapeutic target in GBM and demonstrate a practical treatment approach.
Insights
NADH dehydrogenase [ubiquinone] 1 alpha subcomplex, 4-like 2 (NDUFA4L2) is upregulated in glioblastoma (GBM), promoting tumor growth. Targeting NDUFA4L2 with apatinib inhibits GBM progression and offers a potential therapeutic strategy.
Area of Science:
- Mitochondrial biology
- Cancer research
- Molecular oncology
Background:
- NADH dehydrogenase [ubiquinone] 1 alpha subcomplex, 4-like 2 (NDUFA4L2) is a Complex I subunit involved in cancer metabolism.
- The role and regulation of NDUFA4L2 in glioblastoma (GBM) remain largely uncharacterized.
Purpose of the Study:
- To investigate the biological function and molecular regulation of NDUFA4L2 in GBM.
- To evaluate NDUFA4L2 as a potential therapeutic target for GBM.
Main Methods:
- Gene knockdown of NDUFA4L2 in GBM cells.
- Analysis of NDUFA4L2 expression and patient survival data.
- In vitro and in vivo experiments using GBM xenografts.
- Assessment of mitophagy and apoptosis induction.
- Evaluation of hypoxia-inducible factor (HIF)-1α inhibition and apatinib treatment.
Main Results:
- NDUFA4L2 is significantly upregulated in GBM, correlating with reduced patient survival.
- NDUFA4L2 knockdown inhibits GBM cell proliferation, enhances apoptosis, and triggers protective mitophagy.
- Combining NDUFA4L2 knockdown with mitophagy blockers significantly increases GBM cell apoptosis and inhibits tumor growth.
- NDUFA4L2 expression in GBM is not directly regulated by HIF-1α.
- Apatinib effectively targets NDUFA4L2 in GBM cells.
Conclusions:
- NDUFA4L2 is a critical driver of GBM progression and a potential therapeutic target.
- Targeting NDUFA4L2, potentially with apatinib, offers a promising treatment strategy for GBM patients.
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