Ras inhibition amplifies cisplatin sensitivity of human glioblastoma

Biochemical and Biophysical Research Communications
Samantha MessinaAntonio Porcellini

Abstract

Resistance to chemotherapy is a common feature of malignant gliomas. This resistance is mediated by receptor tyrosine kinase (RTK)-regulated signaling. p21-Ras protein is pivotal in the propagation of the signal originated from many RTKs. Our aim was to investigate whether inhibition of Ras pathway affects the response to cisplatin in malignant gliomas. We found an enhanced sensitivity to cisplatin of two glioblastoma cell lines expressing dominant negative Ras. Moreover, DN-Ras expressing cells, implanted in nude mice, resulted in being extremely sensitive to cisplatin. The growth of all the tumors was significantly inhibited by combining DN-Ras adenovirus infection with cisplatin treatment. The majority of glioma cells expressing DN-Ras underwent apoptosis in response to cisplatin. In vivo, DN-Ras alone did not influence the growth of tumors, suggesting that the effects of Ras-inhibition observed in vitro could not be extrapolated in vivo. The survival signal pathway transduced by Ras was essentially mediated by inhibition of caspase-9 cleavage via PI3K/Akt.

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Citations

Nov 15, 2008·The Journal of Biological Chemistry·Piro LitoJ Justin McCormick
May 31, 2014·Cell Death & Disease·L GalluzziG Kroemer
Feb 28, 2006·Gynecologic Oncology·Qinghua WuJahn M Nesland
Jul 21, 2016·Cancer Investigation·Hung-Yen LeeNasreen Najmunnisa
Jan 26, 2020·Cancer Letters·Chun-Wen ZhengEn-Min Li

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