Progression-Related Loss of Stromal Caveolin 1 Levels Mediates Radiation Resistance in Prostate Carcinoma via the Apoptosis Inhibitor TRIAP1

Abstract

Tumour resistance to chemo- and radiotherapy, as well as molecularly targeted therapies, limits the effectiveness of current cancer treatments. We previously reported that the radiation response of human prostate tumours is critically regulated by CAV1 expression in stromal fibroblasts and that loss of stromal CAV1 expression in advanced tumour stages may contribute to tumour radiotherapy resistance. Here we investigated whether fibroblast secreted anti-apoptotic proteins could induce radiation resistance of prostate cancer cells in a CAV1-dependent manner and identified TRIAP1 (TP53 Regulated Inhibitor of Apoptosis 1) as a resistance-promoting CAV1-dependent factor. TRIAP1 expression and secretion was significantly higher in CAV1-deficient fibroblasts and secreted TRIAP1 was able to induce radiation resistance of PC3 and LNCaP prostate cancer cells in vitro, as well as of PC3 prostate xenografts derived from co-implantation of PC3 cells with TRIAP1-expressing fibroblasts in vivo. Immunohistochemical analyses of irradiated PC3 xenograft tumours, as well as of human prostate tissue specimen, confirmed that the characteristic alterations in stromal-epithelial CAV1 expression were accompanied by increased TRIAP1 levels after radiation in xenograft tumours and within advanced prostate cancer tissues, potentially mediating resistance to radiation treatment. In conclusion, we have determined the role of CAV1 alterations potentially induced by the CAV1-deficient, and more reactive, stroma in radio sensitivity of prostate carcinoma at a molecular level. We suggest that blocking TRIAP1 activity and thus avoiding drug resistance may offer a promising drug development strategy for inhibiting resistance-promoting CAV1-dependent signals.

Caveolin-1 regulates the ASMase/ceramide-mediated radiation response of endothelial cells in the context of tumor–stroma interactions

“…Silencing of CAV1 in cancer cells themselves was already shown to re-sensitize tumor cells to RT-induced apoptosis [48][49][50][51] . Even in PCa, which is characterized by increased CAV1 expression levels in malignant epithelial cells at advanced, more radioresistant disease stages, a reduction of CAV1 was suited to achieve tumor cell radiosensitization 30,37 . We demonstrated here that RT induced a significant growth delay and cell death in PCa spheroids when co-cultured with CAV1-deficient ECs that were at least partially mediated by RT-induced ASMase/ceramide signaling in EC.…”

“…As an increase in epithelial CAV1 (together with a loss of stromal CAV1) has been linked to PCa RT resistance 30,37 , we decided to explore a potential link between the levels of ceramide, ASMase, and CAV1 as well as their respective stromal-epithelial distribution, in tissue specimen of human PCa (Fig. 7).…”

“…CAV1 gained increasing attention in cancer therapy because CAV1 expression levels strongly increase in malignant epithelial cells of many solid tumors at advanced tumor stages [28][29][30] . In parallel, a loss of stromal CAV1 could be observed, which correlated with tumor progression and therapy resistance, especially in prostate cancer (PCa), and may therefore be suited as a prognostic marker 29,[31][32][33] .…”

TRIAP1 knockdown sensitizes non‐small cell lung cancer to ionizing radiation by disrupting redox homeostasis

“…This suggests that the toxic effects of radiation are enhanced. Ketteler et al . unveiled that TRIAP1 (secreted by fibroblasts) was taken up by adjacent prostate cancer cells, PC3 and LNCaP, resulting in a pronounced cancer radioresistance .…”

“…This suggests that the toxic effects of radiation are enhanced. Ketteler et al 35 unveiled that TRIAP1 (secreted by fibroblasts) was taken up by adjacent prostate cancer cells, PC3 and LNCaP, resulting in a pronounced cancer radioresistance. 36 Studies have illustrated that TRIAP1 exerts antiapoptotic effects via its interaction with HSP70, which inhibits cytochrome c to activate the apoptotic protease activating factor 1 and in turn the downstream caspase-9.…”