Survivin, a Member of the Inhibitor of Apoptosis Family, Is Induced by Photodynamic Therapy and Is a Target for Improving Treatment Response

Abstract

We observed that photodynamic therapy (PDT) induces the expression and phosphorylation of the inhibitor of apoptosis (IAP) protein survivin in murine and human cancer cells and tumors. Survivin inhibits caspase-9, blocks apoptosis, and is associated with resistance to chemotherapy and radiation. Survivin is a client protein for the 90-kDa heat shock protein (Hsp-90), and the binding of survivin to Hsp-90 assists in the maturation, proper folding, assembly, and transport of this IAP protein. A derivative of the antibiotic geldanamycin, 17-allylamino-17-demethoxygeldanamycin (17-AAG), interferes with proper binding of client proteins, such as survivin, to Hsp-90 and leads to misfolding of client proteins, ubiquination, and proteasome degradation. We hypothesized that PDT efficacy may be reduced by treatment-mediated expression and phosphorylation of survivin, and therefore, targeting the survivin pathway could increase PDT responsiveness. To address this hypothesis, we examined cellular and molecular responses following exposure to PDT, 17-AAG, and the combination of PDT plus 17-AAG in human BT-474 breast cancer cells using Photofrin and NPe6 as photosensitizers. Cells treated with the combination of PDT and 17-AAG exhibited decreased expression of the Hsp-90 client proteins phosphorylated survivin, phosphorylated Akt, and Bcl-2. The decreased expression of these client proteins was accompanied by higher apoptotic indexes and increased cytotoxicity. To confirm a specific role for survivin in modulating PDT, we used a human melanoma cell line, YUSAC2/T34A-C4, stably transfected with an inducible dominant-negative survivin gene under the control of a tetracycline-regulated (tet-off) promoter. PDT treatment of melanoma cells expressing the dominant-negative survivin resulted in increased cleavage of the caspase substrate poly(ADP-ribose) polymerase, apoptosis, and cytotoxicity when compared with results following PDT of the same melanoma cell line expressing wild-type survivin. These results show for the first time that targeting survivin and possibly other Hsp-90 client proteins improves in vitro PDT responsiveness and suggest that manipulation of the antiapoptotic pathway maintained by survivin may enhance PDTmediated cancer therapy. [Cancer Res 2007;67(10):4989-95]

Effects of potential calcium sensing receptor inducers on promoting chemosensitivity of human colon carcinoma cells

“…We examined survivin, TS, and E-cadherin to ß-catenin/TCF4 signaling system in the current study, since those proteins play pivotal roles in colon carcinoma cells in terms of cell malignancy, differentiation, apoptosis, and responsiveness to FOLFIRI, the current regimen for colon cancer. Survivin is an anti-apoptotic protein that blocks apoptotic process in carcinoma cells, whereas resistance to apoptosis is a key mechanism for the cells to resist anticancer drugs (29)(30)(31). TS is a key enzyme involved in the de novo synthesis of DNA and is the molecular target of 5-FU (32,33).…”

Effects of HSP27 downregulation on PDT resistance through PDT-induced autophagy in head and neck cancer cells

“…Some of these signals act as mediators or promoters of apoptosis, while some signals act as stress responses that promote the repair of or increase the resistance to PDT-induced damage (16). Effects of PDT may be determined by balancing death and survival for cancer therapy resistance mechanisms (17,18). In previous study, HSP70 was found to regulate the apoptosis of chemoresistant cells by inhibiting pro-apoptotic proteins (19,20).…”

Melanoma Cell Signalling: Looking Beyond RAS-RAF-MEK

“…Photodynamic therapy (PDT) and cytotoxic agents were found to enhance survivin (member of the inhibitor of apoptotic protein family) expression which desensitised these cells to apoptosis (Ferrario et al, 2007;Qiu et al, 2005). Other anti-apoptotic factors (e.g.…”

“…Since Hsp90 interacts with several oncognenic proteins involved in melanoma, disrupting their interaction may reduce the stability of these pro-tumour proteins (Powers and Workman, 2006). In melanoma and breast cancer cells, survivin induced PDT resistance (Ferrario et al, 2007). PDT increased survivin expression and phosphorylation both in vitro (BA mouse breast cancer cells) and in vivo (C3H mice transplanted with BA cells).…”

“…The blockade of EGFR caused a decrease in both AKT and survivin expression which resulted in cell death. Therefore, high ERK/AKT activity in combination with increased survivin levels lead to melanoma cell survival (Ferrario et al, 2007;Qiu et al, 2005). Since, both survivin and AKT are Hsp90 client proteins and have been implicated in PDT-and chemo-resistant melanoma cells, targeting Hsp90 may have beneficial effects (Qiu et al, 2005).…”