Cyclin D1 repressor domain mediates proliferation and survival in prostate cancer.

Regulation of the androgen receptor (AR) is critical to prostate cancer (PCa) development; therefore, AR is the first line therapeutic target for disseminated tumors. Cell cycle-dependent accumulation of cyclin D1 negatively modulates the transcriptional regulation of AR through discrete, CDK4-independent mechanisms. The transcriptional corepressor function of cyclin D1 resides within a defined motif termed repressor domain (RD), and it was hypothesized that this motif could be utilized as a platform to develop new strategies for blocking AR function. Here, we demonstrate that expression of the RD peptide is sufficient to disrupt AR transcriptional activation of multiple, prostate-specific AR target genes. Importantly, these actions are sufficient to specifically inhibit S-phase progression in AR-positive PCa cells, but not in AR-negative cells or tested AR-positive cells of other lineages. As expected, impaired cell cycle progression resulted in a suppression of cell doubling. Additionally, cell death was observed in AR-positive cells that maintain androgen dependence and in a subset of castrate-resistant PCa cells, dependent on Akt activation status. Lastly, the ability of RD to cooperate with existing hormone therapies was examined, which revealed that RD enhanced the cellular response to an AR antagonist. Together, these data demonstrate that RD is sufficient to disrupt AR-dependent transcriptional and proliferative responses in PCa, and can enhance efficacy of AR antagonists, thus establishing the impetus for development of RD-based mimetics

Using ICP-OES and SEM-EDX in biosorption studies

We have compared the analytical results obtained by inductively coupled plasma optical emission spectroscopy (ICP-OES) and by scanning electron microscopy with an energy dispersive X-ray analytical system (SEM-EDX) in order to explore the mechanism of metal ions biosorption by biomass using two independent methods. The marine macroalga Enteromorpha sp. was enriched with Cu(II), Mn(II), Zn(II), and Co(II) ions via biosorption, and the biosorption capacity of alga determined from the solution and biomass composition before and after biosorption process was compared. The first technique was used to analyze the composition of the natural and metal-loaded biomass, and additionally the composition of the solution before and after biosorption. The second technique was used to obtain a picture of the surface of natural and metal ion-loaded macroalgae, to map the elements on the cell wall of dry biomass, and to determine their concentration before and after biosorption. ICP-OES showed a better precision and lower detection limit than EDX, but SEM-EDX gave more information regarding the sample composition of Enteromorpha sp. Both techniques confirmed that biosorption is a surface phenomenon, in which alkali and alkaline earth metal ions were exchanged by metal ions from aqueous solution

Removal of cationic pollutants from water by xanthated corn cob: optimization, kinetics, thermodynamics, and prediction of purification process

The removal of Cr(III) ions and methylene blue (MB) from aqueous solutions by xanthated corn cob (xCC) in batch conditions was investigated. The sorption capacity of xCC strongly depended of the pH, and increase when the pH rises. The kinetics was well fitted by pseudo-second order and Chrastil’s model. Sorption of Cr(III) ions and MB on xCC was rapid during the first 20 min of contact time and, thereafter, the biosorption rate decrease gradually until reaching equilibrium. The maximum sorption capacity of 17.13 and 83.89 mg g-1 for Cr(III) ions and MB, respectively was obtained at 40 °C, pH 5 and sorbent dose 4 g dm-3 for removal of Cr(III) ions and 1 g dm-3 for removal of MB. The prediction of purification process was successfully carried out and the verification of theoretically calculated amounts of sorbent was confirmed by using packed-bed column laboratory system with recirculation of the aqueous phase. The wastewater from chrome plating industry was successfully purified, i.e. after 40 min concentration of Cr(III) ions was decreased lower than 0.1 mg dm-3. Also, removal of MB from the river water was successfully carried out and after 40 min removal efficiency was about 94 %

DNA-PKcs-Mediated Transcriptional Regulation Drives Prostate Cancer Progression and Metastasis.

Emerging evidence demonstrates that the DNA repair kinase DNA-PKcs exerts divergent roles in transcriptional regulation of unsolved consequence. Here, in vitro and in vivo interrogation demonstrate that DNA-PKcs functions as a selective modulator of transcriptional networks that induce cell migration, invasion, and metastasis. Accordingly, suppression of DNA-PKcs inhibits tumor metastases. Clinical assessment revealed that DNA-PKcs is significantly elevated in advanced disease and independently predicts for metastases, recurrence, and reduced overall survival. Further investigation demonstrated that DNA-PKcs in advanced tumors is highly activated, independent of DNA damage indicators. Combined, these findings reveal unexpected DNA-PKcs functions, identify DNA-PKcs as a potent driver of tumor progression and metastases, and nominate DNA-PKcs as a therapeutic target for advanced malignancies

DNA Repair in Prostate Cancer: Biology and Clinical Implications

CONTEXT: For more precise, personalized care in prostate cancer (PC), a new classification based on molecular features relevant for prognostication and treatment stratification is needed. Genomic aberrations in the DNA damage repair pathway are common in PC, particularly in late-stage disease, and may be relevant for treatment stratification. OBJECTIVE: To review current knowledge on the prevalence and clinical significance of aberrations in DNA repair genes in PC, particularly in metastatic disease. EVIDENCE ACQUISITION: A literature search up to July 2016 was conducted, including clinical trials and preclinical basic research studies. Keywords included DNA repair, BRCA, ATM, CRPC, prostate cancer, PARP, platinum, predictive biomarkers, and hereditary cancer. EVIDENCE SYNTHESIS: We review how the DNA repair pathway is relevant to prostate carcinogenesis and progression. Data on how this may be relevant to hereditary cancer and genetic counseling are included, as well as data from clinical trials of PARP inhibitors and platinum therapeutics in PC. CONCLUSIONS: Relevant studies have identified genomic defects in DNA repair in PCs in 20-30% of advanced castration-resistant PC cases, a proportion of which are germline aberrations and heritable. Phase 1/2 clinical trial data, and other supporting clinical data, support the development of PARP inhibitors and DNA-damaging agents in this molecularly defined subgroup of PC following success in other cancer types. These studies may be an opportunity to improve patient care with personalized therapeutic strategies. PATIENT SUMMARY: Key literature on how genomic defects in the DNA damage repair pathway are relevant for prostate cancer biology and clinical management is reviewed. Potential implications for future changes in patient care are discussed

A patient-derived explant (PDE) model of hormone-dependent cancer

Breast and prostate cancer research to date has largely been predicated on the use of cell lines in vitro or in vivo. These limitations have led to the development of more clinically relevant models, such as organoids or murine xenografts that utilize patient-derived material; however, issues related to low take rate, long duration of establishment, and the associated costs constrain use of these models. This study demonstrates that ex vivo culture of freshly resected breast and prostate tumor specimens obtained from surgery, termed patient-derived explants (PDEs), provides a high-throughput and cost-effective model that retains the native tissue architecture, microenvironment, cell viability, and key oncogenic drivers. The PDE model provides a unique approach for direct evaluation of drug responses on an individual patient's tumor, which is amenable to analysis using contemporary genomic technologies. The ability to rapidly evaluate drug efficacy in patient-derived material has high potential to facilitate implementation of personalized medicine approaches.Margaret M. Centenera, Theresa E. Hickey, Shalini Jindal, Natalie K. Ryan, Preethi Ravindranathan, Hisham Mohammed, Jessica L. Robinson, Matthew J. Schiewer, Shihong Ma, Payal Kapur, Peter D. Sutherland, Clive E. Hoffmann, Claus G. Roehrborn, Leonard G. Gomella, Jason S. Carroll, Stephen N. Birrell, Karen E. Knudsen, Ganesh V. Raj, Lisa M. Butler, Wayne D. Tille

Novel Oncogenic Transcription Factor Cooperation in RB-Deficient Cancer

The retinoblastoma tumor suppressor (RB) is a critical regulator of E2F-dependent transcription, controlling a multitude of protumorigenic networks including but not limited to cell-cycle control. Here, genome-wide assessment of E2F1 function after RB loss in isogenic models of prostate cancer revealed unexpected repositioning and cooperation with oncogenic transcription factors, including the major driver of disease progression, the androgen receptor (AR). Further investigation revealed that observed AR/E2F1 cooperation elicited novel transcriptional networks that promote cancer phenotypes, especially as related to evasion of cell death. These observations were reflected in assessment of human disease, indicating the clinical relevance of the AR/E2F1 cooperome in prostate cancer. Together, these studies reveal new mechanisms by which RB loss induces cancer progression and highlight the importance of understanding the targets of E2F1 function. SIGNIFICANCE: This study identifies that RB loss in prostate cancer drives cooperation between AR and E2F1 as coregulators of transcription, which is linked to the progression of advanced disease

A Novel Role for DNA-PK in Metabolism by Regulating Glycolysis in Castration Resistant Prostate Cancer

Published first January 24, 2022.Purpose: DNA-dependent protein kinase catalytic subunit (DNA-PKcs, herein referred as DNA-PK) is a multifunctional kinase of high cancer relevance. DNA-PK is deregulated in multiple tumor types, including prostate cancer, and is associated with poor outcomes. DNA-PK was previously nominated as a therapeutic target and DNA-PK inhibitors are currently undergoing clinical investigation. Although DNA-PK is well studied in DNA repair and transcriptional regulation, much remains to be understood about the way by which DNA-PK drives aggressive disease phenotypes. Experimental Design: Here, unbiased proteomic and metabolomic approaches in clinically relevant tumor models uncovered a novel role of DNA-PK in metabolic regulation of cancer progression. DNA-PK regulation of metabolism was interrogated using pharmacologic and genetic perturbation using in vitro cell models, in vivo xenografts, and ex vivo in patient-derived explants (PDE). Results: Key findings reveal: (i) the first-in-field DNA-PK protein interactome; (ii) numerous DNA-PK novel partners involved in glycolysis; (iii) DNA-PK interacts with, phosphorylates (in vitro), and increases the enzymatic activity of glycolytic enzymes ALDOA and PKM2; (iv) DNA-PK drives synthesis of glucosederived pyruvate and lactate; (v) DNA-PK regulates glycolysis in vitro, in vivo, and ex vivo; and (vi) combination of DNA-PK inhibitor with glycolytic inhibitor 2-deoxyglucose leads to additive anti-proliferative effects in aggressive disease. Conclusions: Findings herein unveil novel DNA-PK partners, substrates, and function in prostate cancer. DNA-PK impacts glycolysis through direct interaction with glycolytic enzymes and modulation of enzymatic activity. These events support energy production that may contribute to generation and/or maintenance of DNA-PK–mediated aggressive disease phenotypes.Emanuela Dylgjeri, Vishal Kothari, Ayesha A. Shafi, Galina Semenova, Peter T. Gallagher, Yi F. Guan, Angel Pang, Jonathan F. Goodwin, Swati Irani, Jennifer J. McCann, Amy C. Mandigo, Saswati Chand, Christopher M. McNair, Irina Vasilevskaya, MatthewJ. Schiewer, Costas D. Lallas, Peter A. McCue, Leonard G. Gomella, Erin L. Seifert, Jason S. Carroll, Lisa M. Butler, Jeff Holst, William K. Kelly, and Karen E. Knudse