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Open Access Publications from the University of California

Scholarly Works (58 results)

  • Thesis
  • Peer Reviewed
UC Irvine Electronic Theses and Dissertations (2020)

Castration-resistant prostate cancer (CRPC) is a lethal disease and its progression is primarily driven by reactivation of androgen receptor (AR) signaling even after treatments with castration and multiple AR pathway inhibitors [CHAPTER 1]. In addition, epigenetic mechanisms, including lysine-specific demethylase 1A (LSD1) overexpression, have recently been appreciated as cell-fate determining drivers of the heterogeneity of CRPC and the associated treatment resistances [CHAPTER 2]. Therefore, we hypothesized that dual targeting of AR and LSD1 might be a more effective therapeutic approach in preventing or delaying the progression of CRPC. Through a series of structural similarity search of flavin adenine dinucleotide (FAD, a co-factor of LSD1) analogs, molecular docking studies and experimental screenings of inhibitors for LSD1 enzymatic activity and AR transcriptional activity, we have discovered for the first time that Sanguinarine, a naturally occurring compound from the root of Sanguinaria canadensis as well as other Fumaria species, is a potent dual inhibitor of both LSD1 and AR [CHAPTER 4]. In vitro Surface Plasmon Resonance (SPR) and in vivo Cellular thermal shift assay (CETSA) assays confirmed that Sanguinarine directly binds to both LSD1 and AR with equal or very close binding affinities. In addition, the growth inhibitory and anti-AR signaling effects of Sanguinarine are partially dependent on the expression levels of LSD1 as shown in LSD1 knockdown and overexpression experiments. To assess the effect of Sanguinarine on CRPC progression, we found that Sanguinarine inhibited the neuroendocrine trans-differentiation of prostate cancer cell lines induced by Dovitinib, a pan—tyrosine kinase inhibitor in prostate cancer clinical trials, both in vitro and in vivo in xenograft models and significantly enhanced the anti-tumor efficacy of Dovitinib [CHAPTER 6]. Furthermore, Sanguinarine more effectively reduce the growth and regeneration of spheroids from stem cell-like prostate cancer cells or cancer initiation cells than bulk prostate cancer cells both in vitro and in an vivo xenograft model and down-regulates the expression of cancer stem cell markers (i.e. .Nanog, Sox2 and Oct4) [CHAPTER 7]. Overall, the results we have gathered demonstrate that Sanguinarine is a structural model as a dual inhibitor of LSD1 and AR for preventing or delay CRPC progression through mechanisms of down-regulation of AR signaling and inhibition of neuroendocrine differentiation and cancer stem cells. Our studies have provided a new strategy for treatment of CRPC.

    Cover page: The discovery of Sanguinarine as a dual-inhibitor of Androgen receptor and lysine-specific demethylase 1A for preventing or delaying lethal prostate cancer progression
    • Article
    • Peer Reviewed
    UC Irvine Previously Published Works (2011)
    Array of new targets for investigation as cancer therapeutics has great potential to grow as new splice-variants are identified and characterized in cancer cell-lines and tumor samples. Tumor-specific splice variants are being discovered at an increasing rate and their functions are also investigated in cancer progression. The tumor-specific splice variants whose expression patterns and activities are successfully characterized may become attractive targets for ablation or splicing modification. The extreme specificity of their expression suggests that a variant-specific treatment may allow for targeting of cancerous cells with minimal impact to healthy tissues. Clinical investigation of applying antisense oligonucleotides to down-regulate mRNAs that contribute to cancer cell survival and to modify splicing patterns in muscular dystrophy has shown promising results. These results show that antisense therapy may be applied effectively and safely in humans. As these treatment strategies continue to improve and novel tumor-specific splice-variants are identified, modification of splicing patterns will become an important field of investigation to develop more effective and safe cancer therapies.
      Cover page: Potential molecular targeting of splice variants for cancer treatmentCreative Commons 'BY' version 4.0 license
      • Article
      • Peer Reviewed
      UC Irvine Previously Published Works (2023)

      Purpose of review

      Castration-resistant prostate cancer (CRPC) is a lethal form of prostate cancer (PCa) due to the development of resistance to androgen deprivation therapy and anti-androgens. Here, we review the emerging role of Wnt signaling in therapeutic resistance of CRPC.

      Recent findings

      Convincing evidence have accumulated that Wnt signaling is aberrantly activated through genomic alterations and autocrine and paracrine augmentations. Wnt signaling plays a critical role in a subset of CRPC and in resistance to anti-androgen therapies. Wnt signaling navigates CRPC through PCa heterogeneity, neuroendocrine differentiation, DNA repair, PCa stem cell maintenance, epithelial-mesenchymal-transition and metastasis, and immune evasion.

      Summary

      Components of Wnt signaling can be harnessed for inhibiting PCa growth and metastasis and for developing novel therapeutic strategies to manage metastatic CRPC. There are many Wnt pathway-based potential drugs in different stages of pre-clinical development and clinical trials but so far, no Wnt signaling-specific drug has been approved by FDA for clinical use in CRPC.
        Cover page: Wnt Signaling and Therapeutic Resistance in Castration-Resistant Prostate Cancer
        • Thesis
        • Peer Reviewed
        UC Irvine Electronic Theses and Dissertations (2018)

        Vitamin E has been the subject of numerous basic and clinical research studies for cancer chemoprevention, which have shown widely varying results. At present, the NIH Office of Dietary Supplements does not consider there to be sufficient evidence for the use of Vitamin E supplementation for cancer prevention. The heterogeneous nature of Vitamin E and the differences in the anti-cancer activities of its components suggests that the study of individual tocopherols may yield more definitive and encouraging results.

        Bladder cancer (BCa) presents an ideal opportunity for the evaluation of tocopherols as novel chemopreventive agents. While a majority of newly diagnosed BCa cases are localized and confined to the initiation site on the interior urothelial lining, the high rate of recurrence necessitates long-term follow-up and increases the need for novel agents that can prevent new tumor initiation. As natural products already present in the diet, with a known safety profile, tocopherols are excellent candidates for application as dietary chemopreventive agents to reduce the recurrence rate of BCa and improve treatment outcomes.

        In this study, I demonstrate that delta-tocopherol is more effective than either of the more common alpha- or gamma- tocopherols at inducing apoptosis in human BCa cell lines. I identified the cause of this effect to be induction of endoplasmic reticulum (ER) stress and the unfolded protein response, leading to death receptor 5 mediated apoptosis. Additionally, delta tocopherol treated cells exhibited an autophagy-like phenotype which, when investigated further, provided novel evidence of endoplasmic reticulum specific, ER stress-related autophagy that remains an emerging field of study. Both xenograft and transgenic mouse studies have confirmed the strong anti-tumor and anti-tumorigenesis efficacy of dietary delta tocopherol administration both at the primary tumor initiation site and at distant sites, with no observed negative side effects.

        As the first study of delta tocopherol as an individual chemopreventive agent in BCa, these results suggest strong potential for the future development and clinical application of dietary delta tocopherol supplementation to improve the lives and treatment outcomes of BCa patients.

          Cover page: Investigating Delta Tocopherol as a Novel Dietary Bladder Cancer Chemopreventive Agent
          • Article
          • Peer Reviewed
          UC Irvine Previously Published Works (2023)
          Cuproptosis, a newly discovered form of programmed cell death, plays a vital role in the occurrence and development of tumors. However, the role of cuproptosis in the bladder cancer tumor microenvironment remains unclear. In this study, we developed a method for predicting the prognostic outcomes and guiding the treatment selection for patients with bladder cancer. We obtained 1001 samples and survival data points from The Cancer Genome Atlas database and Gene Expression Omnibus database. Using cuproptosis-related genes (CRGs) identified in previous studies, we analyzed CRG transcriptional changes and identified two molecular subtypes, namely high- and low-risk patients. The prognostic features of eight genes (PDGFRB, COMP, GREM1, FRRS1, SDHD, RARRES2, CRTAC1, and HMGCS2) were determined. The CRG molecular typing and risk scores were correlated with clinicopathological features, prognosis, tumor microenvironment cell infiltration characteristics, immune checkpoint activation, mutation burden, and chemotherapy drug sensitivity. Additionally, we constructed an accurate nomogram to improve the clinical applicability of the CRG_score. qRT-PCR was used to detect the expression levels of eight genes in bladder cancer tissues, and the results were consistent with the predicted results. These findings may help us to understand the role of cuproptosis in cancer and provide new directions for the design of personalized treatment and prediction of survival outcomes in patients with bladder cancer.
            Cover page: Comprehensive analysis of cuproptosis-related genes on bladder cancer prognosis, tumor microenvironment invasion, and drug sensitivity
            • Article
            • Peer Reviewed
            UC Irvine Previously Published Works (2012)
            The incidence of human urinary bladder cancer increases markedly with age, suggesting a mechanistic connection between aging and bladder carcinogenesis and a potential use of anti-aging agents in bladder cancer chemoprevention. Rhodiola rosea, growing in high altitude or cold regions of the world, has been reported to have anti-aging effects in Drosophila. We demonstrated that a R. rosea extract and one of its bioactive components, salidroside, inhibited the growth of bladder cancer cell lines with a minimal effect on nonmalignant bladder epithelial cells TEU-2. Interestingly, the R. rosea extract and salidroside component exhibited a selective ability to inhibit the growth of p53 knockout primary mouse embryo fibroblasts (p53-/- MEFs) compared to their wild-type counterparts. The growth inhibitory effects of the R. rosea extract and salidroside were, however, attenuated in TSC2 and p53 double knock MEFs (TSC2-/-, p53-/- MEFs), suggesting that TSC2 protein is, at least in part, required for the growth inhibitory effects of the R. rosea extract and salidroside. The R. rosea extract and salidroside treatment of UMUC3 cells resulted in an increase of AMP-activated protein kinase (AMPK)-α phosphorylation and a decrease of 4E-BP1 phosphorylation, leading to increased binding of 4E-BP1 to m7 GTP. These results indicate that the R. rosea extract and salidroside inhibit translation initiation. Furthermore, both the R. rosea extract and salidroside treatment of UMUC3 cells caused a significant percentage of cells undergoing autophagy. Therefore, the R. rosea extract and salidroside deserve further study as novel agents for chemoprevention of bladder carcinogenesis.
              Cover page: Rhodiola rosea extracts and salidroside decrease the growth of bladder cancer cell lines via inhibition of the mTOR pathway and induction of autophagyCreative Commons 'BY' version 4.0 license
              • Article
              • Peer Reviewed
              UC Irvine Previously Published Works (2022)
              Non-muscle-invasive bladder cancer (NMIBC) has one of the highest recurrence rates among all solid cancers and the highest lifetime treatment cost per patient. Therefore, the development of chemoprevention strategies for reducing the occurrence and recurrence of NMIBC as well as its burdens on the healthcare system is valuable. Our aim was to determine whether flavokawain A (FKA), a kava chalcone isolated from the kava plant, can target the in vivo activated Ha-ras pathway for prevention and treatment of NMIBC. UPII-mutant Ha-ras transgenic mice that develop papillary urothelial cell carcinoma were fed orally with vehicle control or FKA-formulated food for 6 months starting at 6 weeks of age. Seventy-nine percent (15/19) of male mice fed with 6 g FKA per kilogram (kg) of food survived beyond the 6 months of treatment, while 31.6% (6/19) of control food-fed male mice survived the 6-month treatment period (p = 0.02). The mean bladder weights in FKA vs. control food-fed mice were 0.216 ± 0.033 vs. 0.342 ± 0.039 g in male mice (p = 0.0413) and 0.043 ± 0.004 vs. 0.073 ± 0.004 g in female mice (p < 0.0001); FKA reduced bladder weight by 37% and 41%, respectively. The tumor burdens, determined by the wet bladder weight, in these mice were inversely related to plasma FKA concentrations. In addition to decreased bladder weight, FKA treatment significantly reduced the incidences of hydronephrosis and hematuria. FKA-treated mice exhibited more well-differentiated tumors in the bladder and ureter. Immunohistochemical analysis of FKA-treated tumors compared to those in the control group revealed fewer Ki-67- and survivin-positive cells and an increased number of p27- and TUNEL-positive cells, indicating that FKA inhibits proliferation and induces apoptosis. Overall, the results suggest that FKA can target the in vivo activated Ha-ras pathway for the prevention and treatment of NMIBC.
                Cover page: Chemoprevention of Urothelial Cell Carcinoma Tumorigenesis by Dietary Flavokawain A in UPII-Mutant Ha-ras Transgenic Mice.Creative Commons 'BY' version 4.0 license
                • Article
                • Peer Reviewed
                UC Irvine Previously Published Works (2017)
                The MDM2 and MDMX oncogenes are overexpressed in various types of human cancer and are highly associated with the initiation, progression, metastasis and chemotherapeutic resistance of these diseases, including prostate cancer. The present study was designed to test a natural MDM2 inhibitor, Inulanolide A (InuA), for anti-prostate cancer activity and to determine the underlying mechanism(s) of action. InuA directly bound to the RING domains of both MDM2 and MDMX with high affinity and specificity and disrupted MDM2-MDMX binding, markedly enhancing MDM2 protein degradation. We further discovered that InuA bound to the DNA binding domain of NFAT1, resulting in marked inhibition of MDM2 transcription. InuA inhibited the proliferation, migration, and invasion of prostate cancer cells, regardless of their p53 status and AR responsiveness. Double knockdown of MDM2 and NFAT1 also revealed that the expression of both of these molecules is important for InuA's inhibitory effects on the proliferation and invasion of prostate cancer cells. In summary, InuA represents a novel class of bifunctional MDM2 inhibitors, and should be further investigated as a candidate lead compound for prostate cancer prevention and therapy.
                  Cover page: Targeting the NFAT1-MDM2-MDMX Network Inhibits the Proliferation and Invasion of Prostate Cancer Cells, Independent of p53 and Androgen
                  • Article
                  • Peer Reviewed
                  UC Irvine Previously Published Works (2016)
                  We have purified physapubescin, a predominant steroidal lactone, from medicinal plant Physalis pubescens L., commonly named as "hairy groundcherry" in English and "Deng-Long-Cao" in Chinese. Von Hippel-Lindau (VHL)-null 786-O, RCC4 and A498 Renal Cell Carcinoma (RCC) cell lines expressing high levels of Hypoxia Inducible Factor (HIF)-2α are more sensitive to physapubescin-mediated apoptosis and growth inhibitory effect than VHL wild-type Caki-2 and ACHN RCC cell lines. Restoration of VHL in RCC4 cells attenuated the growth inhibitory effect of physapubescin. Physapubescin decreases the expression of HIF-2α and increases the expression of CCAAT/enhancer-binding protein homologus protein (CHOP), which leads to up-regulation of death receptor 5 (DR5), activation of caspase-8 and -3, cleavage of poly (ADP-Ribose) polymerase (PARP) and apoptosis. Under hypoxia conditions, the apoptotic and growth inhibitory effects of physapubescin are further enhanced. Additionally, physapubescin synergizes with TNF-related apoptosis-inducing ligand (TRAIL) for markedly enhanced induction of apoptosis in VHL-null 786-O cells but not in VHL wild-type Caki-2 cells. Physapubescin significantly inhibited in vivo angiogenesis in the 786-O xenograft. Physapubescin as a novel agent for elimination of VHL-null RCC cells via apoptosis is warranted for further investigation.
                    Cover page: Physapubescin selectively induces apoptosis in VHL-null renal cell carcinoma cells through down-regulation of HIF-2α and inhibits tumor growthCreative Commons 'BY' version 4.0 license
                    • Article
                    • Peer Reviewed
                    UC Irvine Previously Published Works (2021)

                    Aim

                    Here, we aim to evaluate the chemopreventive efficacy of kava root extracts (KRE) in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice and investigate potential molecular targets of kavalactones, the main components of kava.

                    Methods

                    TRAMP mice were administrated with KRE formulated food for different periods of time, and then the incidences of high-grade prostatic intraepithelial neoplasia (HG-PIN) and adenocarcinomas and tumor burdens were compared between vehicle control and KRE food fed groups. In addition, the inhibitory effect of the KRE and kavalactones on monoamine oxidase A (MAO-A) and lysine-specific demethylase 1 (LSD1) enzyme activities were examined by commercially available inhibitor screening kits. Histone H3 lysine 9 dimethylation was also evaluated in prostate cancer cells and tumor tissues using Western blotting analysis.

                    Results

                    Dietary feeding of 0.3% and 0.6% KRE to TRAMP mice from ages of 6 weeks to 12 weeks inhibited HG-PIN by 43.5% and 59.7%, respectively, and prostate adenocarcinoma by 53.5% and 66.4%, respectively. In addition, 0.6% KRE fed TRAMP mice from ages of 6 weeks to 24 weeks exhibited a significant reduction of genitourinary weight (a surrogate of tumor burden) by 54.5% and reduced body weight gain. Furthermore, the KRE and kavalactones showed a significant inhibition of LSD1 and MAO-A enzyme activities.

                    Conclusion

                    Our results suggest that consumption of kava products through diet can delay prostate cancer development and progression and that kavalactones may be a new structure model for developing a potent dual inhibitor of LSD1 and MAO-A.
                      Cover page: Kava root extracts hinder prostate cancer development and tumorigenesis by involvement of dual inhibition of MAO-A and LSD1
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