In spite of the mounting evidence supporting a predominant pro-tumor role of the IAPs in prostate cancer, in the present study, according to the Spearman’s test, only few associations were found between the expression of these proteins and adverse clinicopathological features. Thus, significant positive correlations were found between cIAP1/2 and pathological T stage, cIAP2 and positive surgical margins, and between Survivin and perineural invasion. Furthermore, we found positive correlations between expression of some caspases and adverse clinicopathological features: procaspase-8 correlated with both clinical and pathological T stages, cleaved caspase-8 correlated with preoperative serum PSA, and caspase-7 correlated with Gleason score and the presence of lymph node metastasis. Although at first glance the associations found for caspases may seem contradictory, some points should be considered. First, the pro-apoptotic activity of caspases mostly relies on their cleaved forms and, therefore, higher levels of procaspases do not necessarily entail enhanced apoptotic signaling. Further, there are recent evidences that caspase-8 could exert a pro-tumor role by inducing cell motility, adhesion and metastasis [18]. In this regard, Finlay et al. [19] demonstrated that caspase-8 is involved in the adhesion-mediated activation of the ERK 1/2 signaling pathway. Using caspase-8-null mouse embryo fibroblasts, Helfer et al. [20] demonstrated that caspase-8 is able to promote cell motility and calpain activity under non apoptotic conditions. Interestingly, it has been shown that the role of caspase-8 on cell motility, adhesion and metastasis is independent of the caspase catalytic activity and has been linked to the phosphorylation of procaspase-8 on tyrosine 380, which prevents its cleavage [20]. In addition to these pro-tumor roles of caspase-8, cells with impaired apoptosis despite displaying continued caspase activation have been shown to secrete mitogenic signals in a manner which is dependent on the catalytic activity of caspases [21]. The persistence of these cells could result in increased proliferation of the neighbor cells and, consequently, promote tumor progression [21]. These less-known functions of caspases could also explain why higher expression levels of some of them have been correlated with a poor prognosis in some cancers [22, 23]. All these pro-tumor activities of caspases should be taken into account in future research.

In the present work, we also found that patients with positive immunostaining for XIAP had a significantly better prognosis compared to negative patients. This result is not surprising, as higher XIAP expression has been reported as a favorable prognostic factor in other cancers [24, 25]. Interestingly, it has been shown that TRAMP (transgenic adenocarcinoma of the mouse prostate) mice deficient in XIAP tend to have a more aggressive disease [26]. In addition, our results are in agreement with a study by Seligson et al. [27] in which higher XIAP expression was also a favorable prognostic factor for biochemical progression after radical prostatectomy. Of note, in that study, despite taking different methodological approaches – regarding the used antibody, the immunostaining scoring and the stratification criteria – XIAP added prognostic value to Gleason score and tumor extension [27], in accordance with the results derived from our multivariate analysis. Therefore, our results add support to previous findings that XIAP may be useful as a predictor of prostate cancer progression, which strongly warrants validation in large prospective studies.

In addition to observations derived from functional studies, the fact that XIAP expression positively associates with a favorable prognosis in some cancers has led to question the pro-tumor role of this IAP. Some authors have argued that this controversy could lie in the initial studies on the anti-apoptotic role of XIAP, which are based on its overexpression in cell lines and the short-term response to different pro-apoptotic stimuli [28]. Thus, when XIAP is stably overexpressed in cell lines at levels comparable to those of tumor cells, it does not protect from apoptosis induced by commonly used chemotherapeutic agents [28]. It has even been recently demonstrated that XIAP is able to mediate cell death through mitochondrial outer membrane permeabilization upon cell detachment [29] or stimulation with resveratrol [30]. It is likely that XIAP functions as an anti- or pro-apoptotic factor, or that is neutral, depending on the scenario. More studies are needed to elucidate the mechanisms accounting for its possible anti-tumor role in patients and its potential as a therapeutic target.

The existing studies on the predictive value of caspases in prostate cancer have focused on assessing the association between the presence of allelic variants of genes encoding for these proteins and the risk of disease or the response to therapy [31, 32]. In the present work, we found that negative expression of either procaspase-3 or cleaved caspase-3 strongly associated with an earlier biochemical progression. As demonstrated in the multivariate Cox models, the prognostic capability of both caspase-3 forms was independent on established prognostic factors – Gleason score and pathological T stage – indicating that they may help to identify patients at high risk of progression. Among the executioner caspases, caspase-3 is thought to be the most determinant in integrating the pro-apoptotic signals coming from both extrinsic and the intrinsic pathways, and ultimately, in triggering the activation of the apoptotic program [3]. Therefore, it is tentative to speculate from our observations that suppression of caspase-3 expression profoundly enhances the survival capability of prostate cancer cells, thus contributing to prostate cancer progression. Strategies aimed to restore or enhance expression of caspases, such as the use of either demethylating agents [33] or the adenovirus-mediated transfer of inducible caspases [34], may be effective for prostate cancer treatment, particularly in those patients lacking tumor caspase-3 expression.