Survivin As a Therapeutic Target for Radiation Sensitization in Lung Cancer

Abstract

Expression of survivin is elevated in most malignancies, especially in radiation-resistant cell lines. In this study, we investigated how radiation affects survivin expression in primary endothelial cells as well as in malignant cell lines. We found that 3 Gy significantly reduced survivin protein level in human umbilical vein endothelial cells (HUVECs) but not in tumor cell lines. Flow cytometry studies suggest that the down-regulation of survivin is independent of cell cycle. In addition, survivin mRNA level was also down-regulatable by irradiation. However, it was abrogated by actinomycin D-mediated inhibition of gene transcription. Luciferase reporter gene assays suggest that irradiation suppressed the survivin promoter. p53 overexpression reduced survivin expression, but overexpression of a p53 mutant failed to abolish the radiation-induced downregulation in HUVECs. Alteration of p53 status in Val138 lung cancer cell line also failed to restore the radiation-inducible down-regulation. Overexpression of survivin in 293 cells prevented apoptosis induced by irradiation and increased cell viability after irradiation. The inhibition of survivin using antisense oligonucleotides caused a significant decrease in cell viability of irradiated H460 lung cancer cells. These data suggest that radiation transcriptionally down-regulates survivin in HUVECs. This regulatory mechanism is defective in malignancies and is not mediated by p53. Survivin overexpression may lead to resistance to radiotherapy by inhibiting apoptosis and enhancing cell viability. The inhibition of survivin results in sensitization of H460 lung cancer cells to radiation. These studies suggest that survivin may be a target for cancer therapy.

Sensitization of pancreatic carcinoma cells for γ-irradiation-induced apoptosis by XIAP inhibition

“…These data provide convincing evidence that blocking XIAP, for example, by small molecule inhibitors, is a promising novel strategy to restore radiosensitivity of pancreatic carcinoma, a prototype cancer that is notoriously resistant to apoptosis. There is mounting evidence that IAPs are involved in determining sensitivity to radiotherapy in human cancers (Rodel et al, 2003;Cao et al, 2004;Lu et al, 2004). To this end, high levels of XIAP or survivin have been associated with resistance to radiotherapy in lung or colorectal carcinoma (Holcik et al, 2000;Rodel et al, 2003;Cao et al, 2004;Lu et al, 2004).…”

“…Apoptosis signaling may be disrupted by deregulated expression and/or function of antiapoptotic molecules, for example 'inhibitor of apoptosis proteins' (Fulda and Debatin, 2006c). IAPs such as X-linked inhibitor of apoptosis (XIAP), cellular inhibitor of apoptosis protein 1 (cIAP1), cIAP2, survivin or livin are expressed at high levels in many human cancers, which has been associated with treatment resistance, for example, resistance to radiotherapy (Salvesen and Duckett, 2002;Rodel et al, 2003;Cao et al, 2004;Lu et al, 2004). Since IAPs block apoptosis at the core of the apoptotic machinery by inhibiting caspases, therapeutic targeting of IAPs may overcome resistance.…”

“…Therefore, there has been much interest in recent years to antagonize IAPs for radiosensitization of human cancers. To this end, survivin or XIAP antisense oligonucleotides were shown to enhance the efficacy of radiotherapy by reducing survival and increasing apoptosis in lung cancer cells Lu et al, 2004). We recently reported that ectopic expression of Smac, an endogenous inhibitor of IAPs, enhanced g-irradiation-induced apoptosis of cancer cells .…”

Centrosome amplification induced by survivin suppression enhances both chromosome instability and radiosensitivity in glioma cells

“…Furthermore, survivin is also involved in radioresistance (Asanuma et al, 2002;Chakravarti et al, 2004;Rodel et al, 2005) and its suppression leads to an enhanced radiosensitivity in various malignant tumour cells (Pennati et al, 2003;Lu et al, 2004;Kappler et al, 2005). However, the mechanisms underlying radiosensitisation are still not well understood.…”

The effects of knockdown of wild-type survivin, survivin-2B or survivin-Δ3 on the radiosensitization in a soft tissue sarcoma cells in vitro under different oxygen conditions

“…5,[16][17][18][19][20] Furthermore, survivin overexpression was associated with radioresistance in tumor cell lines. [21][22][23][24][25][26] The knockdown of survivin by ribozymes resulted in an increase of sensitivity of mt-p53 melanoma cells to irradiation. 22 Moreover, transfection of survivin made radiosensitive pancreatic cancer cells more radioresistant and inhibited the activity of caspase-3.…”