## 4 Discussion  
In the last three decades, our increased understanding of tumor biology has increasingly aided the unraveling of appreciable metabolic complexity of malignant cells and cancerization, regardless of cancer type or histological sub-type [17; 18]. It is of translational relevance that certain cancerous cells are more dependent on specific oncogenic, metabolic, or onometabolic pathways for survival than others within this evolving metabolic landscape. For instance, it is well established that the activation of AR is essential for the growth of prostate cancer; more so, castration-resistant prostate cancer (CRPC) is largely addicted  
Figure 7: Inhibition of SRD5A1 with Dutasteride synergistically enhances the anticancer potential of low dose Docetaxel, reduces metastatic burden, and confers survival advantage, in vivo. Graphical representation of the correlation between HSD17B2, HSD17B3, SHBG, or SRD5A1 and **(A)** Gleason score, or **(B)** sample group in the GSE70768 PCA cohort. **(C)** Visualization of the in silico protein-compound association query using the DrugBank database. **(D)** Photo-images and dose–response curves showing individual and synergistic effects of Docetaxel and/or Dutasteride on the proliferation/viability of PC-3 cells. **(E)** Schema of our tumor xenograft in vivo model. **(F)** Photo-image and line graph of the effect of SHBG_OE, sgSRD5A1, or docetaxel–dutasteride combination treatment on tumor volume in mice inoculated with PC-3 cells. Kaplan–Meier curves showing the effect of SHBG_OE, sgSRD5A1, or docetaxel–dutasteride combination treatment on the **(G)** overall, and **(H)** metastasis-free survival of mice inoculated with PC-3 cells. **(I)** Notched box and whiskers plot of the effect of SHBG_OE, sgSRD5A1, or docetaxel–dutasteride combination treatment on the number of metastatic nodules in mice inoculated with PC-3 cells. to functional AR, with several mechanisms suggested to explain this addiction, including AR point mutations, gene amplification, and/or overexpression [19]. Interestingly, there is accruing evidence of the enhanced conversion of the weak adrenal androgen called androstenedione to testosterone by steroidogenic effectors of androgen metabolism in patients with metastatic CRPC compared to primary treatment-naive PCa [20]. Upregulated androgenic enzymes within the tumor bulk facilitates enhanced conversion of adrenal steroids into gonadal steroids like testosterone and DHT, with associated AR-mediated transcriptional activation consequently driving castration resistance [19; 20]. The present study demonstrated that the differential expression of HSD17B2, HSD17B3, SHBG, and SRD5A1 in patients with different PCa grades is suggestive of a dysregulated androgenic-signal-driven oncogenicity in patients with PCa, where intracellular signaling skewed towards a dominant SRD5A1/HSD17B3 at the expense of SHBG/HSD17B2 signaling drives enhanced cancerization, and may inform therapeutic decision making and management strategy for patients with PCa (Figure 1). This is therapeutically relevant within the context of the centrality of ADT to the management of metastatic and recurrent PCa, as well as the critical role of androgen hormones androgenic signaling in the development and progression of PCa, especially as CRPC, once attributed to hormone refraction, is increasingly shown to be driven by sex steroid hormones [21; 22]. In partial congruence with our findings, [PERSON] et al. reported that, compared to normal adjacent prostate tissues, the expression of HSD17B3 and SRD5A2 was markedly increased in benign prostatic hyperplasia (BPH) tissues, HSD17B2 expression was significantly decreased in all samples, and SRD5A2 transcript level was upregulated in BPH and PCa compared to the normal adjacent prostate tissues [23].