A gain of function paradox: Targeted therapy for glioblastoma associated with abnormal NHE9 expression

内吞作用 癌症研究 受体 受体酪氨酸激酶 内体 医学 细胞凋亡 细胞生物学 生物 化学 内科学 生物化学
作者
Ashley E. Pall,Lena Juratli,Dhyana Guntur,K. Bandyopadhyay,Kalyan C. Kondapalli
出处
期刊:Journal of Cellular and Molecular Medicine [Wiley]
卷期号:23 (11): 7859-7872 被引量:10
标识
DOI:10.1111/jcmm.14665
摘要

Abstract Glioblastoma (GBM) is the most frequent and inevitably lethal primary brain cancer in adults. It is recognized that the overexpression of the endosomal Na + /H + exchanger NHE9 is a potent driver of GBM progression. Patients with NHE9 overexpression have a threefold lower median survival relative to GBM patients with normal NHE9 expression, using available treatment options. New treatment strategies tailored for this GBM subset are much needed. According to the prevailing model, NHE9 overexpression leads to an increase in plasma membrane density of epidermal growth factor receptors (EGFRs) which consequently enhances GBM cell proliferation and migration. However, this increase is not specific to EGFRs. In fact, the hallmark of NHE9 overexpression is a pan‐specific increase in plasma membrane receptors. Paradoxically, we report that this gain of function in NHE9 can be exploited to effectively target GBM cells for destruction. When exposed to gold nanoparticles, NHE9 overexpressing GBM cells accumulated drastically high amounts of gold via receptor‐mediated endocytosis, relative to control. Irradiation of these cells with near‐infrared light led to apoptotic tumour cell death. A major limitation for delivering therapeutics to GBM cells is the blood‐brain barrier (BBB). Here, we demonstrate that macrophages loaded with gold nanoparticles can cross the BBB, deliver the gold nanoparticles and effect the demise of GBM cells. In combination with receptor tyrosine kinase inhibition, we show this approach holds great promise for a new GBM‐targeted therapy.
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