The clinico pathological features and survival in serous endometrial cancers.

Background & Introduction: Serous cancers are a biologically aggressive variety of endometrial cancer (EC) with a high rate of recurrence and mortality among all the subtypes. Herein we describe our experience with serous endometrial cancer. Objective: This study was conducted to identify the clinicopathological characteristics, treatment modalities and survival outcomes in women diagnosed with serous endometrial malignancies. Methods: This was a retrospective descriptive analysis of data on patients diagnosed with serous endometrial tumours between January 2010 to September 2019 in our institute collected from electronic medical records. Descriptive statistics such as proportions, means and standard deviations and Cox regression hazards model on risk factors were performed. Survival was plotted by Kaplan-Meier curves. Results: During the study period, 32 (5.7%) patients out of 564 diagnosed cases of endometrial cancer had serous histology. The mean age at diagnosis was 62.5 years (SD 7.6) while mean BMI was 26.4 kg/m2 (SD 4.6). Staging laparotomy was done in 27(84%) of the patients. Advanced stages (III and IV) were detected in 16 patients (50%) at primary surgery.Adjuvant chemo therapy and radiation was received by 21(65.6%) patients therapy. Out of 32 patients, 13 (40%) developed recurrence while another 13 expired. Stage at diagnosis and type of adjuvant therapy were important factors in determining the outcome. Median recurrence free and overall survival was 22(95% CI 1.4-42) and 36 months (95% CI 10.1-61.8) respectively. Conclusion: Serous endometrial cancers are an intrusive subtype of EC. Comprehensive surgical staging with optimal cytoreduction should be aimed at. Adequate upfront molecular categorization of these tumors is mandated. Adjuvant therapy with chemotherapy and radiation is given in postoperative setting. Targeted therapies and immunotherapy could be considered in recurrences.

A longitudinal study of sexual health and quality of life in endometrial carcinoma survivors.

OBJECTIVES: This study aimed to assess sexual health and quality of life (QoL) in endometrial cancer survivors and the factors influencing these variables. METHODS: A mixed method design comprising quantitative (cohort design) and qualitative (face-to-face interviews) aspects was chosen. A total of 132 patients who underwent surgery alone, surgery followed by adjuvant vaginal brachytherapy, or surgery followed by chemotherapy and radiation were included. Female Sexual Function Index (FSFI) and Functional Assessment of Cancer Therapy General (FACT-G) questionnaires were used to assess the participants' sexual health and QoL at 6 months and 1 year post-treatment. Multivariate logistic regression models were used to analyze the factors associated with general and sexual well-being. RESULTS: At 1 year, 89% of the participants still had low sexual function scores. Survivors over 50 years (OR 284.7, 95% CI 13 to 364, p<0.001) and educated below graduate level (OR 26.8, 95% CI 2 to 370, p=0.014) had low sexual function scores. Patients who had surgery alone had better QoL than those who received adjuvant radiation. Women who had surgery, chemotherapy, and radiation had the lowest QoL scores (OR 6.4, 95% CI 2.1 to 19.5, p=0.001). All scores improved with time. CONCLUSIONS: This study demonstrated the high prevalence of low sexual function and poor QoL in endometrial cancer survivors. There was a communication gap between the women and their partners as well as their healthcare providers. This study highlights the need for discussion about the survivors' sexual well-being and QoL.

Repurposing ketoconazole as an exosome directed adjunct to sunitinib in treating renal cell carcinoma.

Renal Cell Carcinoma (RCC) is the most common form of kidney cancer, with clear cell RCC (ccRCC) representing about 85% of all RCC tumors. There are limited curable treatments available for metastatic ccRCC because this disease is unresponsive to conventional targeted systemic pharmacotherapy. Exosomes (Exo) are small extracellular vesicles (EVs) secreted from cancer cells with marked roles in tumoral signaling and pharmacological resistance. Ketoconazole (KTZ) is an FDA approved anti-fungal medication which has been shown to suppress exosome biogenesis and secretion, yet its role in ccRCC has not been identified. A time-course, dose-dependent analysis revealed that KTZ selectively decreased secreted Exo in tumoral cell lines. Augmented Exo secretion was further evident by decreased expression of Exo biogenesis (Alix and nSMase) and secretion (Rab27a) markers. Interestingly, KTZ-mediated inhibition of Exo biogenesis was coupled with inhibition of ERK1/2 activation. Next, selective inhibitors were employed and showed ERK signaling had a direct role in mediating KTZ's inhibition of exosomes. In sunitinib resistant 786-O cells lines, the addition of KTZ potentiates the efficacy of sunitinib by causing Exo inhibition, decreased tumor proliferation, and diminished clonogenic ability of RCC cells. Our findings suggest that KTZ should be explored as an adjunct to current RCC therapies.

Complications and Outcomes of Diaphragm Surgeries in Epithelial Ovarian Malignancies.

To achieve optimal debulking, cytoreductive surgery often involves diaphragm stripping. We describe our complications and survival outcomes after diaphragm surgery in epithelial ovarian cancer. A retrospective analysis on patients with advanced stage epithelial ovarian cancer between January 2012 and September 2019. The details of the diaphragmatic resections and stripping and their complications were looked into. During the study period, 616 patients with epithelial ovarian cancers were operated of which, 81 (13.2%) had diaphragm surgery. The majority underwent diaphragm stripping (60%) while 33% had resection and 7% cases had diaphragmatic nodule excision. Optimal debulking was achieved in 89% of cases. The complexity of surgery was intermediate in 64% of patients and complex in 33% as per Aletti's scoring. Mean operating time was 300 min (SD113). Moderate to severe pleural effusion was seen in 26 (32. %) patients necessitating pleural tapping in 16% and single lumen pleurex catheter insertion in 11%. Median recurrence-free and overall survival were 22 (95% CI 16.9-27) and 32 months (95% CI 25.5-38) respectively. Diaphragm stripping and resection is an important step in achieving optimal debulking of advanced and recurrent ovarian cancer. Diaphragmatic disease clearance is a necessary skill to be acquired by the gynaecologic oncology surgeons. Choosing the patients correctly and anticipation of complications can reduce morbidity and mortality.

Circular Migration and Precarity: Perspectives from Rural Bihar.

Migration and mobilities are vastly underestimated in India. In particular, circular migration remains poorly captured as circular migrants move back and forth between source and destination regions. Based on survey data from rural Bihar, an important source region of migration in India, this paper finds that a vast majority of migrants work and live in precarity in predominantly urban and prosperous destinations across India. However, those at the lowest rungs of the social and economic ladder in source regions-the scheduled castes and scheduled tribes, other backward classes I and the labouring class-are the worst off at destination; they are part of the most precarious shorter-term migration streams, earn the lowest incomes, have the poorest conditions of work, and live in the harshest circumstances. The paper shows that social and economic hierarchies, and in turn, precarity in source region is reproduced at destination, and, thus, there is little evidence that spatial mobility is associated with social mobility. Focusing on migrants' location, work, employment, income, housing, and access to basic services at destination, the paper foregrounds migrant precarity and adds to a small body of empirical literature that is significant in understanding the spatial and structural elements of circular migration in India and in turn, the migration crisis that emerged as a result of the economic shock of the COVID 19 pandemic.

Isolation, characterisation and detection of breath-derived extracellular vesicles.

The physical characterisation, capture and detection of extracellular vesicles (EVs) and exosomes derived from breath condensate is reported. Breath-derived EVs were isolated from breath condensate and captured on a gold substrate using two complimentary methods. The characterised and isolated EVs were detected using surface plasmon resonance (SPR) and electrochemical impedance spectroscopy (EIS). EIS was done using aptamers as a targeting moiety and showed a larger change in resistance between dilute concentrations of EVs (less than 7 µg/mL).This is the first report of EVs and exosomes isolated and characterised from breath. In addition, EVs from a non-invasive and easily available source such as breath opens up further avenues in the detection of pulmonary diseases.

High-throughput screening identified selective inhibitors of exosome biogenesis and secretion: A drug repurposing strategy for advanced cancer.

Targeting exosome biogenesis and release may have potential clinical implications for cancer therapy. Herein, we have optimized a quantitative high throughput screen (qHTS) assay to identify compounds that modulate exosome biogenesis and/or release by aggressive prostate cancer (PCa) CD63-GFP-expressing C4-2B cells. A total of 4,580 compounds were screened from the LOPAC library (a collection of 1,280 pharmacologically active compounds) and the NPC library (NCGC collection of 3,300 compounds approved for clinical use). Twenty-two compounds were found to be either potent activators or inhibitors of intracellular GFP signal in the CD63-GFP-expressing C4-2B cells. The activity of lead compounds in modulating the secretion of exosomes was validated by a tunable resistive pulse sensing (TRPS) system (qNano-IZON) and flow cytometry. The mechanism of action of the lead compounds in modulating exosome biogenesis and/or secretion were delineated by immunoblot analysis of protein markers of the endosomal sorting complex required for transport (ESCRT)-dependent and ESCRT-independent pathways. The lead compounds tipifarnib, neticonazole, climbazole, ketoconazole, and triademenol were validated as potent inhibitors and sitafloxacin, forskolin, SB218795, fenoterol, nitrefazole and pentetrazol as activators of exosome biogenesis and/or secretion in PC cells. Our findings implicate the potential utility of drug-repurposing as novel adjunct therapeutic strategies in advanced cancer.

Estradiol-ERß2 signaling axis confers growth and migration of CRPC cells through TMPRSS2-ETV5 gene fusion.

Estrogen receptor beta (ERß) splice variants are implicated in prostate cancer (PC) progression; however their underlying mechanisms remain elusive. We report that non-canonical activation of estradiol (E2)-ERß2 signaling axis primes growth, colony-forming ability and migration of the androgen receptor (AR)-null castration-resistant PC (CRPC) cells under androgen-deprived conditions (ADC). The non-classical E2-ERß2 mediates phosphorylation and activation of Src-IGF-1R complex, which in turn triggers p65-dependent transcriptional upregulation of the androgen-regulated serine protease TMPRSS2:ETV5a/TMPRSS2:ETV5b gene fusions under ADC. siRNA silencing of TMPRSS2 and/or ETV5 suggests that TMPRSS2:ETV5 fusions facilitates the E2-ERß induced growth and migration effects via NF-κB-dependent induction of cyclin D1 and MMP2 and MMP9 in PC-3 cells. Collectively, our results unravel the functional significance of oncogenic TMPRSS2:ETV5 fusions in mediating growth and migration of E2-ERß2 signaling axis in CRPC cells. E2-ERß2 signaling axis may have significant therapeutic and prognostic implications in patients with CRPC.

Manumycin A suppresses exosome biogenesis and secretion via targeted inhibition of Ras/Raf/ERK1/2 signaling and hnRNP H1 in castration-resistant prostate cancer cells.

Emerging evidence links exosomes to cancer progression by the trafficking of oncogenic factors and neoplastic reprogramming of stem cells. This necessitates identification and integration of functionally validated exosome-targeting therapeutics into current cancer management regimens. We employed quantitative high throughput screen on two libraries to identify exosome-targeting drugs; a commercially available collection of 1280 pharmacologically active compounds and a collection of 3300 clinically approved compounds. Manumycin-A (MA), a natural microbial metabolite, was identified as an inhibitor of exosome biogenesis and secretion by castration-resistant prostate cancer (CRPC) C4-2B, but not the normal RWPE-1, cells. While no effect was observed on cell growth, MA attenuated ESCRT-0 proteins Hrs, ALIX and Rab27a and exosome biogenesis and secretion by CRPC cells. The MA inhibitory effect is primarily mediated via targeted inhibition of the Ras/Raf/ERK1/2 signaling. The Ras-dependent MA suppression of exosome biogenesis and secretion is partly mediated by ERK-dependent inhibition of the oncogenic splicing factor hnRNP H1. Our findings suggest that MA is a potential drug candidate to suppress exosome biogenesis and secretion by CRPC cells.

Nanotechnology combined therapy: tyrosine kinase-bound gold nanorod and laser thermal ablation produce a synergistic higher treatment response of renal cell carcinoma in a murine model.

OBJECTIVE: To investigate tyrosine kinase inhibitors (TKI) and gold nanorods (AuNRs) paired with photothermal ablation in a human metastatic clear cell renal cell carcinoma (RCC) mouse model. Nanoparticles have been successful as a platform for targeted drug delivery in the treatment of urological cancers. Likewise, the use of nanoparticles in photothermal tumour ablation, although early in its development, has provided promising results. Our previous in vitro studies of nanoparticles loaded with both TKI and AuNRs and activated with photothermal ablation have shown significant synergistic cell kill greater than each individual arm alone. This study is a translation of our initial findings to an in vivo model. MATERIALS AND METHODS: Immunologically naïve nude mice (athymic nude-Foxn1nu ) were injected subcutaneously bilaterally in both flanks (n = 36) with 2.5 × 106 cells of a human metastatic renal cell carcinoma cell line (RCC 786-O). Subcutaneous xenograft tumours developed into 1-cm palpable nodules. AuNRs encapsulated in human serum albumin protein (HSA) nanoparticles were synthesised with or without a TKI and injected directly into the tumour nodule. Irradiation was administered with an 808-nm light-emitting diode laser for 6 min. Mice were humanely killed 14 days after irradiation; tumours were excised, formalin fixed, paraffin embedded, and evaluated for size and the percentage of necrosis by a genitourinary pathologist. The untreated contralateral flank tumours were used as controls. RESULTS: In mice that did not receive irradiation, TKI alone yielded 4.2% tumour necrosis on the injected side and administration of HSA-AuNR-TKI alone yielded 11.1% necrosis. In the laser-ablation models, laser ablation alone yielded 62% necrosis and when paired with HSA-AuNR there was 63.4% necrosis. The combination of laser irradiation and HSA-AuNR-TKI had cell kill rate of 100%. CONCLUSIONS: In the absence of laser irradiation, TKI treatment alone or when delivered via nanoparticles produced moderate necrosis. Irradiation with and without gold particles alone also improves tumour necrosis. However, when irradiation is paired with gold particles and drug-loaded nanoparticles, the combined therapy showed the most significant and synergistic complete tumour necrosis of 100% (P < 0.05). This study illustrates the potential of combination nanotechnology as a new approach in the treatment of urological cancers.

Identification of microRNA signature and potential pathway targets in prostate cancer.

Prostate cancer (PC) is the most common and the second leading cause of cancer-related death among American men. Early diagnosis is a prerequisite to improving therapeutic benefits. However, the current clinical biomarkers for PC do not reliably decipher indolent PC from other urogenital disorders. Thus, effective clinical intervention necessitates development of new biomarkers for early detection of PC. The present study aimed to identify the miRNA signature in organ-confined (Gleason Score 6) prostate tumors. MicroRNA (miRNA/miR) array analysis identified 118 upregulated and 73 downregulated miRNAs in microdissected tumors in comparison to matched neighboring normal prostate epithelium. The miRs-Plus-A1083, -92b-5p, -18a-3p, -19a-3p, -639, -3622b-3p, -3189-3p, -155-3p, -410, -1179, 548b-5p, and -4469 are predominantly expressed (7-11-fold), whereas miRs-595, 4490, -3120-5p, -1299, -21-5p, -3677-3, -let-7b-5p, -5189, 3-121-5p, -4518, -200a-5p, -3682-5p, -3689d, -3149 represent the most downregulated (12-113-fold) miRNAs in microdissected prostate tumors. The array expression profile of selected miRNA signature and their potential mRNA targets was validated by qRT-PCR analysis in PC cell lines. Integrated in silico and computational prediction analyses demonstrated that the dysregulated miRNA signature map to key regulatory factors involved in tumorigenesis, including cell cycle, apoptosis, and p53 pathways. The newly identified miRNA signature has potential clinical utility as biomarkers, prognostic indicators, and therapeutic targets for early detection of PC. Further studies are needed to assess the functional significance and clinical usefulness of the identified miRNAs. Impact Statement To our knowledge his is the first study of identifying miRNA signatures in microdissected indolent (Gleason score 6) prostate cancer in comparison to matched normal prostate epithelium. By employing in silico and computational prediction analysis, the study provides a landscape of potential miRNA targets and key cellular pathways involved in prostate tumorigenesis. Identification if miRNAs and their relevant targets and pathways pave the way for underpinning their mechanistic role of miRNAs in human prostate tumorigenesis, and possibly other human cancers. Importantly, the outcome of the study has important clinical implications for the management of prostate cancer, including the use of miRNA(s) as biomarkers for early detection of prostate cancer.

Effect of adipose tissue-derived stem cell injection in a rat model of urethral fibrosis.

INTRODUCTION: We sought to evaluate the therapeutic effect of adi-pose tissue-derived stem cells (ADSCs) in a rat model of urethral fibrosis. METHODS: Eighteen (18) male Sprague-Dawley rats (300‒350 g) were divided into three groups: (1) sham (saline injection); (2) urethral fibrosis group (10 µg transforming growth factor beta 1 (TGF-ß1) injection); and (3) ADSCs group (10 µg TGF-ß1 injection plus 2 × 105 ADSCs). Rat ADSCs were harvested from rat inguinal fat pads. All study animals were euthanized at two weeks after urethral injection. Following euthanasia, rat urethral tissue was harvested for histologic evaluation. Type I and III collagen levels were quantitated by Western blot analysis. RESULTS: TGF-ß1 injection induced significant urethral fibrosis and increased collagen type I and III expression (p<0.05). Significant decrease in submucosal fibrosis and collagen type I and III expression were noted in the ADSCs group compared with the urethral fibrosis group (p<0.05). TGF-ß1 induced fibrotic changes were ameliorated by injection of ADSCs. CONCLUSIONS: Local injection of ADSCs in a rat model of urethral fibrosis significantly decreased collagen type I and III. These findings suggest that ADSC injection may prevent scar formation and potentially serve as an adjunct treatment to increase the success rate of primary treatment for urethral stricture disease. Further animal and clinical studies are needed to confirm these results.

Nelfinavir targets multiple drug resistance mechanisms to increase the efficacy of doxorubicin in MCF-7/Dox breast cancer cells.

Development of multidrug resistance (MDR) remains a significant problem in cancer chemotherapy and underscores the importance of using chemosensitizers. Well known MDR mechanisms include: (i) upregulation of drug-efflux; (ii) increased signaling via AKT; and (iii) decreased apoptosis. Therefore, chemosensitizers should target multiple resistance mechanisms. We investigated the efficacy of nelfinavir (NFV), a clinically approved anti-HIV drug, in increasing doxorubicin (DOX) toxicity in a MDR breast cancer cell line, MCF-7/Dox. As compared to parental MCF-7 cells, the MCF-7/Dox were 15-20 fold more resistant to DOX-induced cytotoxicity at 48 h post-exposure (DOX IC50 = 1.8 µM vs. 32.4 µM). Coexposures to NFV could significantly (p < 0.05) decrease DOX-IC50 in MCF-7/Dox cells. Multiple exposures to physiologic concentrations of NFV (2.25 µM or 6.75 µM) decreased DOX-IC50 by 21-fold and 50-fold, respectively. Interestingly, although single exposure to NFV transiently induced P-glycoprotein (P-gp) levels, multiple treatments with NFV inhibited both P-gp expression and efflux function, which increased intracellular DOX concentrations. Single exposure to NFV augmented the markers of cell-survival (AKT) and autophagy (LC3-II), whereas multiple exposures enabled suppression of both total AKT (t-AKT) and insulin like growth factor-1 (IGF-1)-induced phosphorylated AKT (p-AKT) levels. Multiple exposures to NFV also resulted in increased unfolded protein response (UPR) transducers, e.g. Grp78, p-PERK, p-eIF2α, and ATF-4; and endoplasmic reticulum (ER) stress induced death sensors, e.g. CHOP & TRIB-3. Multiple exposures to NFV also abrogated the mitogenic effects of IGF-1. In mice carrying MCF-7/Dox tumor xenografts, intraperitoneal (i.p.) injection of NFV (20 mg/kg/day) and DOX (2 mg/kg/twice/wk) decreased tumor growth more significantly (p < 0.01) than either agent alone. Immunohistochemical (IHC) analysis revealed decreased p-AKT and Ki-67 levels. Thus, NFV overcomes MDR in breast cancer cells and should be tested as an adjunct to chemotherapy.

Dysregulation of miR-212 Promotes Castration Resistance through hnRNPH1-Mediated Regulation of AR and AR-V7: Implications for Racial Disparity of Prostate Cancer.

PURPOSE: The causes of disproportionate incidence and mortality of prostate cancer among African Americans (AA) remain elusive. The purpose of this study was to investigate the mechanistic role and assess clinical utility of the splicing factor heterogeneous nuclear ribonucleoprotein H1 (hnRNP H1) in prostate cancer progression among AA men. EXPERIMENTAL DESIGN: We employed an unbiased functional genomics approach coupled with suppressive subtractive hybridization (SSH) and custom cDNA microarrays to identify differentially expressed genes in microdissected tumors procured from age- and tumor grade-matched AA and Caucasian American (CA) men. Validation analysis was performed in independent cohorts and tissue microarrays. The underlying mechanisms of hnRNPH1 regulation and its impact on androgen receptor (AR) expression and tumor progression were explored. RESULTS: Aberrant coexpression of AR and hnRNPH1 and downregulation of miR-212 were detected in prostate tumors and correlate with disease progression in AA men compared with CA men. Ectopic expression of miR-212 mimics downregulated hnRNPH1 transcripts, which in turn reduced expression of AR and its splice variant AR-V7 (or AR3) in prostate cancer cells. hnRNPH1 physically interacts with AR and steroid receptor coactivator-3 (SRC-3) and primes activation of androgen-regulated genes in a ligand-dependent and independent manner. siRNA silencing of hnRNPH1 sensitized prostate cancer cells to bicalutamide and inhibited prostate tumorigenesis in vivo CONCLUSIONS: Our findings define novel roles for hnRNPH1 as a putative oncogene, splicing factor, and an auxiliary AR coregulator. Targeted disruption of the hnRNPH1-AR axis may have therapeutic implications to improve clinical outcomes in patients with advanced prostate cancer, especially among AA men.

Collagenase Clostridium histolyticum (Xiaflex) for the Treatment of Urethral Stricture Disease in a Rat Model of Urethral Fibrosis.

OBJECTIVE: To evaluate the treatment effect of collagenase Clostridium histolyticum (CCH) in a rat model of urethral fibrosis. MATERIALS AND METHODS: Thirty male Sprague-Dawley rats (300-350 g) were divided into 5 groups. The rat urethra was injected with normal saline in the sham group and, in the other 4 groups, the rat urethra was injected with 10 µg of transforming growth factor beta 1 to create fibrosis of the urethra. Two weeks following transforming growth factor beta 1 injection, the rats were injected with varying doses of CCH or vehicles, depending on their group. The rats were then euthanized at 4 weeks after CCH or vehicle injection. Urethral tissue was harvested for histologic and molecular analyses. Type I and III collagen levels were evaluated by Western blot analysis. RESULTS: There was urethral fibrosis and to significant increase in collagen type I and III expressions in the urethral fibrosis group compared with the sham group (P <.05). Urethral injection of CCH appeared to be safe and significantly reduce urethral fibrosis as well as collagen type I and III expressions in the high-dose CCH treatment groups when compared with the treatment control group (P <.01). CONCLUSION: This study demonstrated a beneficial effect of CCH injections in a rat model of urethral fibrosis. These findings suggest a potential role for CCH as a therapeutic option in urethral stricture patients and warrant further investigation.

Selective targeting of FAK-Pyk2 axis by alpha-naphthoflavone abrogates doxorubicin resistance in breast cancer cells.

Despite an initial positive response, breast cancer cells inevitably acquire resistance to doxorubicin (Dox). Alpha-naphthoflavone (ANF) is a well-known chemopreventive agent; however, its anti-cancer properties have not been established. We examined the therapeutic efficacy of ANF in doxorubicin-resistant MCF-7 (MCF-7/Dox) breast cancer cells and investigated its underlying molecular mechanisms of action. MCF-7/Dox cells expressed constitutively active forms of the tyrosine kinases: focal adhesion kinase (FAK-Y397) and protein tyrosine kinase 2 beta (Pyk2- Y579/580) compared with parental MCF-7 cells. ANF significantly enhanced the sensitivity of MCF-7/Dox cells to Dox cytotoxicity in vitro and when co-administered in vivo. This ANF-mediated chemosensitization has dual mechanisms of action: (a) intracellular Dox retention via suppression of P-glycoprotein pump activity, and (b) inhibition of clonogenic cell survival via de-phosphorylation of FAK, Pyk2, and EGF-induced Akt in MCF-7/Dox cells and tumor xenografts. Because of its strong chemosensitization action, broad safety profile, and health benefits, ANF is an attractive anti-cancer drug with therapeutic implications to circumvent drug resistance in breast cancer patients.

Nrf1 and Nrf2 transcription factors regulate androgen receptor transactivation in prostate cancer cells.

Despite androgen deprivation therapy (ADT), persistent androgen receptor (AR) signaling enables outgrowth of castration resistant prostate cancer (CRPC). In prostate cancer (PCa) cells, ADT may enhance AR activity through induction of oxidative stress. Herein, we investigated the roles of Nrf1 and Nrf2, transcription factors that regulate antioxidant gene expression, on hormone-mediated AR transactivation using a syngeneic in vitro model of androgen dependent (LNCaP) and castration resistant (C4-2B) PCa cells. Dihydrotestosterone (DHT) stimulated transactivation of the androgen response element (ARE) was significantly greater in C4-2B cells than in LNCaP cells. DHT-induced AR transactivation was coupled with higher nuclear translocation of p65-Nrf1 in C4-2B cells, as compared to LNCaP cells. Conversely, DHT stimulation suppressed total Nrf2 levels in C4-2B cells but elevated total Nrf2 levels in LNCaP cells. Interestingly, siRNA mediated silencing of Nrf1 attenuated AR transactivation while p65-Nrf1 overexpression enhanced AR transactivation. Subsequent studies showed that Nrf1 physically interacts with AR and enhances AR's DNA-binding activity, suggesting that the p65-Nrf1 isoform is a potential AR coactivator. In contrast, Nrf2 suppressed AR-mediated transactivation by stimulating the nuclear accumulation of the p120-Nrf1 which suppressed AR transactivation. Quantitative RT-PCR studies further validated the inductive effects of p65-Nrf1 isoform on the androgen regulated genes, PSA and TMPRSS2. Therefore, our findings implicate differential roles of Nrf1 and Nrf2 in regulating AR transactivation in PCa cells. Our findings also indicate that the DHT-stimulated increase in p65-Nrf1 and the simultaneous suppression of both Nrf2 and p120-Nrf1 ultimately facilitates AR transactivation in CRPC cells.