Survivin as a Radioresistance Factor, and Prognostic and Therapeutic Target for Radiotherapy in Rectal Cancer

Abstract

Apoptosis levels have been shown to predict tumor response to preoperative radiochemotherapy in rectal cancer. Recently, the prominent role of survivin, a structurally unique member of the inhibitor of apoptosis protein family, has been shown in colorectal cancer tumorigenesis and prognosis. In this study, we investigated whether survivin plays a direct role in mediating radiation resistance. We used short interfering RNA molecules to decrease survivin in radioresistant SW480 and intermediately radioresistant HCT-15 colorectal cancer cells. This resulted in a significant decrease of survivin mRNA and protein expression with a maximum at 24 to 48 hours after transfection. If irradiated during this sensitive period, an increased percentage of apoptotic cells and an increased caspase 3/7 activity in parallel with a decreased cell viability and a reduced clonogenic survival was shown. These effects were more pronounced in the radioresistant SW480 cell line with a radiation-induced cytotoxicity enhancement factor at 10% and 50% survival of 1.8 to 2.2 for SW480 and 1.5 to 1.7 for HCT-15, respectively. Furthermore, transfection with survivin short interfering RNA increased levels of G 2 -M arrest and levels of DNA double-strand breaks in irradiated cells. These observations indicate that cell cycle and DNA repair mechanisms may be associated with apoptosis induction in tumor cells that are otherwise resistant to killing by radiation. In a translational study of 59 patients with rectal cancer treated with a combination of radiotherapy and chemotherapy, increased survivin expression was inversely related to the levels of apoptosis, and was also associated with a significantly higher risk of a local tumor recurrence. (Cancer Res 2005; 65(11): 4881-7)

Achaete-scute like 2 (ascl2) is a target of Wnt signalling and is upregulated in intestinal neoplasia

“…Both survivin and cdc25b are reported to be clinically important in colorectal cancer. Survivin is known target of Wnt signalling (Zhang et al, 2001) and a putative radioresistance factor in rectal cancer, which may predict local failure of rectal malignancies after chemoradiotherapy and surgical resection (Rodel et al, 2005). cdc25b is overexpressed in 56% of colorectal cancers and expression may predict overall survival (Hernandez et al, 2001).…”

“…No effect of ascl2 knockdown was seen in HCT116 cells, which do not express ascl2 RNA. Survivin and cdc25b are reported to be targets of Wnt signalling, that are overexpressed in colorectal cancer compared to normal colon and promote progression through the G2/M checkpoint (Hernandez et al, 2001;Zhang et al, 2001;Rodel et al, 2005). Therefore, it was hypothesized that the G2/M arrest seen on knockdown of ascl2 might be secondary to the transcriptional regulation of survivin and/or cdc25b by ASCL2.…”

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

“…This was associated with decreased clonogenic survival. 24 We found that suppression of survivin resulted in a significant radiosensitization and in an increase in activity of caspases-3/-7 in cell line A-204 (wt-p53), but not in the cell line US 8-93 (mt-p53). 28 Little is known about the splice variants of survivin.…”

“…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.…”