Farnesyltransferase inhibitor, R115777, reverses the resistance of human glioma cell lines to ionizing radiation

Abstract

We investigated for the first time the ability of farnesyltransferase inhibitors (FTI) to radiosensitize human glioma. For this, human glioma cell lines were treated with the specific FTI, R115777, 48 hr prior to a 2Gy irradiation. The treatment with R115777 decreased by 45% the SF2 value of the more radioresistant glioma cell lines (SF763 and U87) without any significant effect on the radioresistance of the radiosensitive ones (SF767 and U251-MG). This radiosensitizer effect was due to the induction of post-mitotic necrotic cell death. We then tested the hypothesis that wild-type Ras or RhoB, which has been proposed as potential FTI target, could control the glioma radioresistance. For this, we expressed inducible dominant negative forms of Ras (RasN17) and RhoB (RhoBN19) in radioresistant U87 glioma cell line and analyzed the survival after irradiation of the obtained clones. While blocking Ras pathways by expression of RasN17 did not affect the SF2 value of the U87 glioma cell line, the expression of RhoBN19 dramatically reduced the cell survival after irradiation of these cells. Taken together, these data demonstrated that RhoB, but not Ras, is implicated in glioma radioresistance. Furthermore, the R115777 differential radiosensitizer effect underlines the potential therapeutic interest of using this drug as a radiosensitizer of human glioma.

The emerging role of miR‐19 in glioma

“…As previously reported, PTEN overexpression leads to an increase in sensitivity to ionizing radiation in glioma cells,60 LRIG1 enhances the sensitivity of radiotherapy in glioma cells by suppressing EGFR/AKT pathway 64. However, RhoB induces radioresistance in glioma cells 65. It has been identified that CtIP is the target gene of miR‐19 and CtIP plays a role in the DNA end resection and homologous recombination in response to DNA damage 66.…”

Farnesylated RhoB inhibits radiation-induced mitotic cell death and controls radiation-induced centrosome overduplication

“…19,20 We demonstrated earlier that expression of the dominant negative form of RhoB, RhoBN19, in FGF-2-expressing HeLa cells 21 or in radioresistant U87 human glioma 7 dramatically reduced cell survival following irradiation of these two cell lines, but this effect was also apparent in U87 xenografts, 22 as previously shown using FTIs. 6,7 Furthermore, inhibiting RhoB in these radioresistant cell lines increased the percentage of cells undergoing mitotic cell death. 6,7 Taken together, these data strongly suggest that the farnesylated form of RhoB may well be at least one of the farnesylated proteins that regulate radiation-induced mitotic cell death.…”

“…While apoptosis is the universal pathway followed by hematopoietic cells after irradiation, mitotic cell death is the characteristic form of death of cells within solid tumors induced by irradiation 1,2 and the major response to exposure to different anticancer drugs. [3][4][5][6][7] It is now accepted that this type of cell death results from aberrant mitoses following irradiation. Such mitoses that fail to produce correct chromosomal segregation lead to the formation of large nonviable cells with several nuclei.…”

“…However, it has since been shown that this class of compounds elicits a radiosensitizing effect not only in mutated-Ras-expressing radioresistant tumor cell lines 11,12 but also in wild-type Ras-expressing radioresistant tumors of the uterine cervix or of glioblastoma cells. 6,7 We have previously demonstrated that this radiosensitizing effect of FTIs on wild-type Rasexpressing cells was due to the induction of radiation-induced mitotic cell death, strongly suggesting that a farnesylated protein might be involved in controlling these mechanisms. 6,7 In terms of identifying this farnesylated protein, the small GTPase ras homolog gene family, member B (RhoB) appears to be potentially a very interesting candidate.…”

“…6,7 We have previously demonstrated that this radiosensitizing effect of FTIs on wild-type Rasexpressing cells was due to the induction of radiation-induced mitotic cell death, strongly suggesting that a farnesylated protein might be involved in controlling these mechanisms. 6,7 In terms of identifying this farnesylated protein, the small GTPase ras homolog gene family, member B (RhoB) appears to be potentially a very interesting candidate. RhoB is a member of the Rho family of GTPases that regulate cytoskeletal actin, focal adhesion formation, proliferation, cell adhesion signaling, receptor-mediated internalization, motility, transformation, invasion, and transcription.…”