**1. Introduction**

Cancer therapeutic resistance occurs through many different mechanisms, including specific genetic and epigenetic changes in the cancer cell itself and/or the respective microenvironment.

The tumour stroma is now recognized as a key player in cancer cell invasiveness, progression and therapy resistance [1–3]. Activated fibroblasts (cancer associated fibroblasts, CAF) are capable of preventing cancer cell apoptosis and induce proliferation, as well as invasion, of surrounding cancer cells via direct stroma-tumour interactions by secreting extracellular matrix components, growth factors and matrix metalloproteinases, among others [4]. Although the exact mechanisms of fibroblast activation remain elusive, the activation or repression of specific genes or proteins within stromal cells has also been correlated with clinical outcome. Within that scenario, the membrane protein Caveolin-1 (CAV1) came into focus as it is highly expressed in many tumours and high CAV1 levels in tumour cells, as well as the downregulation of stromal CAV1, were shown to correlate with cancer progression, invasion and metastasis and thus, a worse clinical outcome [4,5]. Loss of stromal CAV1 can even be used as a prognostic marker, for example, in breast and prostate cancer patients [6–9]. Data on the CAV1-dependent epithelia-stroma crosstalk indicates that stromal CAV1 possesses tumour-suppressor properties, whereas loss of stromal CAV1 fosters malignant epithelial cell resistance by evading apoptosis [5,10]. Stromal loss of CAV1 is particularly prominent in epithelial prostate cancer, where loss of CAV1 in the stroma correlates with high Gleason score, presence of metastasis and pronounced resistance to chemotherapy and radiotherapy [6,8,11,12]. However, a detailed mechanism explaining how CAV1-deficient fibroblasts foster therapy resistance of malignant prostate cancer cells remains elusive. An improved understanding of the molecular basis of resistance will inevitably lead to the clinical assessment of rational drug combinations in selected patient populations.

An important mechanism by which cancer cells acquire drug resistance is by apoptosis evasion [3] and apoptosis inhibiting proteins have been described in both the development of cancer [13] and drug resistance [14]. TP53-regulated inhibitor of apoptosis 1 (TRIAP1, also known as p53-inducible cell-survival factor, p53CSV) is a small, 76 amino acids long, evolutionary conserved protein [15]. TRIAP1 was first characterized as a p53-inducible cell survival factor [16]. A genetic screen further identified TRIAP1 as a pathway-specific regulator of the cellular response to p53 activation [17]. Mechanistically, TRIAP1 modulates the apoptotic pathways through interaction with HSP70, inhibition of the interaction of cytochrome c with the apoptotic protease activating factor 1 and activation of the downstream caspase-9, thus resulting in increased resistance by inhibiting apoptosis and permitting DNA damage repair [15,16].

In this study, we aimed at determining the role of CAV1 alterations potentially induced by stromal CAV1-deficiency for the radio sensitivity of prostate cancer on molecular level and identified the apoptosis inhibitor TRIAP1 as a CAV1-dependent fibroblastic secreted factor, fostering radio resistance of malignant prostate epithelial cells.

### **2. Material and Methods**
