Browsing by Subject "Prostatic neoplasms"
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Item Coordination between the eIF2 kinase GCN2 and p53 signaling supports purine metabolism and the progression of prostate cancer(American Association for the Advancement of Science, 2024) Cordova, Ricardo A.; Sommers, Noah R.; Law, Andrew S.; Klunk, Angela J.; Brady, Katherine E.; Goodrich, David W.; Anthony, Tracy G.; Brault, Jeffrey J.; Pili, Roberto; Wek, Ronald C.; Staschke, Kirk A.; Biochemistry and Molecular Biology, School of MedicineCancers invoke various pathways to mitigate external and internal stresses to continue their growth and progression. We previously reported that the eIF2 kinase GCN2 and the integrated stress response are constitutively active in prostate cancer (PCa) and are required to maintain amino acid homeostasis needed to fuel tumor growth. However, although loss of GCN2 function reduces intracellular amino acid availability and PCa growth, there is no appreciable cell death. Here, we discovered that the loss of GCN2 in PCa induces prosenescent p53 signaling. This p53 activation occurred through GCN2 inhibition-dependent reductions in purine nucleotides that impaired ribosome biogenesis and, consequently, induced the impaired ribosome biogenesis checkpoint. p53 signaling induced cell cycle arrest and senescence that promoted the survival of GCN2-deficient PCa cells. Depletion of GCN2 combined with loss of p53 or pharmacological inhibition of de novo purine biosynthesis reduced proliferation and enhanced cell death in PCa cell lines, organoids, and xenograft models. Our findings highlight the coordinated interplay between GCN2 and p53 regulation during nutrient stress and provide insight into how they could be targeted in developing new therapeutic strategies for PCa.Item Corrigendum to "Structure-function studies of the bHLH phosphorylation domain of TWIST1 in prostate cancer cells" [Neoplasia 17 (2014) 85](Elsevier, 2024) Gajula, Rajendra P.; Chettiar, Sivarajan T.; Williams, Russell D.; Nugent, Katriana; Kato, Yoshinori; Wang, Hailun; Malek, Reem; Taparra, Kekoa; Cades, Jessica; Annadanam, Anvesh; Yoon, A-Rum; Fertig, Elana; Firulli, Beth A.; Mazzacurati, Lucia; Burns, Timothy F.; Firulli, Anthony B.; An, Steven S.; Tran, Phuoc T.; Pediatrics, School of MedicineThe authors regret an accidental duplication in one of the softagar clonogenic phase contrast photomicrographs for Myc-CaP + Vector cells that was brought to our attention in Fig. 4C. This was an accidental error, and the photomicrographs were removed as they were simply representative images and not used for the quantification displayed later in the figure. Furthermore, the accompanying figure legend has been corrected to reflect this change (changes indicated in bolded text). This error does not affect the interpretation of the data in the manuscript, but the authors would like to apologize for any inconvenience caused.Item Development and preliminary validation of the Brief Self-Compassion Inventory(Public Library of Science, 2023-05-12) Chinh, Kelly; Wu, Wei; Johns, Shelley A.; Stutz, Patrick V.; McGrew, John H.; Mosher, Catherine E.; Psychology, School of ScienceResearch and clinical interest in self-compassion has grown due to its associations with physical and mental health benefits. Widely used measures of self-compassion have conceptual and psychometric limitations that warrant attention. The purpose of this project was to develop a new self-compassion measure, the Brief Self-Compassion Inventory (BSCI), and test its psychometric properties. We developed items for the BSCI based on theory, prior research, and expert and cancer patient feedback. The BSCI was then tested with adults diagnosed with breast, gastrointestinal, lung, or prostate cancer (N = 404). Confirmatory factor analysis suggested a unidimensional structure, and internal consistency reliability was excellent. Construct validity of the BSCI was established through its correlations with psychological variables hypothesized to be related to self-compassion, such as mindfulness, acceptance of cancer, and other coping strategies. Furthermore, measurement invariance testing of the BSCI indicated that it could be used across patients of varying genders, cancer types, and stages of illness. In conclusion, the 5-item BSCI was determined to be psychometrically sound and suitable for use with adults of varying genders, cancer types, and stages of disease. The measure warrants testing with other medical and nonclinical populations.Item Emergency department involvement in the diagnosis of cancer among older adults: a SEER-Medicare study(Oxford University Press, 2024) Thompson, Caroline A.; Sheridan, Paige; Metwally, Eman; Peacock Hinton, Sharon; Mullins, Megan A.; Dillon, Ellis C.; Thompson, Matthew; Pettit, Nicholas; Kurian, Allison W.; Pruitt, Sandi L.; Lyratzopoulos, Georgios; Emergency Medicine, School of MedicineBackground: Internationally, 20% to 50% of cancer is diagnosed through emergency presentation, which is associated with lower survival, poor patient experience, and socioeconomic disparities, but population-based evidence about emergency diagnosis in the United States is limited. We estimated emergency department (ED) involvement in the diagnosis of cancer in a nationally representative population of older US adults, and its association with sociodemographic, clinical, and tumor characteristics. Methods: We analyzed Surveillance, Epidemiology, and End Results Program-Medicare data for Medicare beneficiaries (≥66 years old) with a diagnosis of female breast, colorectal, lung, and prostate cancers (2008-2017), defining their earliest cancer-related claim as their index date, and patients who visited the ED 0 to 30 days before their index date to have "ED involvement" in their diagnosis, with stratification as 0 to 7 or 8 to 30 days. We estimated covariate-adjusted associations of patient age, sex, race and ethnicity, marital status, comorbidity score, tumor stage, year of diagnosis, rurality, and census-tract poverty with ED involvement using modified Poisson regression. Results: Among 614 748 patients, 23% had ED involvement, with 18% visiting the ED in the 0 to 7 days before their index date. This rate varied greatly by tumor site, with breast cancer at 8%, colorectal cancer at 39%, lung cancer at 40%, and prostate cancer at 7%. In adjusted models, older age, female sex, non-Hispanic Black and Native Hawaiian or Other Pacific Islander race, being unmarried, recent year of diagnosis, later-stage disease, comorbidities, and poverty were associated with ED involvement. Conclusions: The ED may be involved in the initial identification of cancer for 1 in 5 patients. Earlier, system-level identification of cancer in non-ED settings should be prioritized, especially among underserved populations.Item Genetic Factors Associated with Prostate Cancer Conversion from Active Surveillance to Treatment(Elsevier, 2022) Jiang, Yu; Meyers, Travis J.; Emeka, Adaeze A.; Folgosa Cooley, Lauren; Cooper, Phillip R.; Lancki, Nicola; Helenowski, Irene; Kachuri, Linda; Lin, Daniel W.; Stanford, Janet L.; Newcomb, Lisa F.; Kolb, Suzanne; Finelli, Antonio; Fleshner, Neil E.; Komisarenko, Maria; Eastham, James A.; Ehdaie, Behfar; Benfante, Nicole; Logothetis, Christopher J.; Gregg, Justin R.; Perez, Cherie A.; Garza, Sergio; Kim, Jeri; Marks, Leonard S.; Delfin, Merdie; Barsa, Danielle; Vesprini, Danny; Klotz, Laurence H.; Loblaw, Andrew; Mamedov, Alexandre; Goldenberg, S. Larry; Higano, Celestia S.; Spillane, Maria; Wu, Eugenia; Carter, H. Ballentine; Pavlovich, Christian P.; Mamawala, Mufaddal; Landis, Tricia; Carroll, Peter R.; Chan, June M.; Cooperberg, Matthew R.; Cowan, Janet E.; Morgan, Todd M.; Siddiqui, Javed; Martin, Rabia; Klein, Eric A.; Brittain, Karen; Gotwald, Paige; Barocas, Daniel A.; Dallmer, Jeremiah R.; Gordetsky, Jennifer B.; Steele, Pam; Kundu, Shilajit D.; Stockdale, Jazmine; Roobol, Monique J.; Venderbos, Lionne D.F.; Sanda, Martin G.; Arnold, Rebecca; Patil, Dattatraya; Evans, Christopher P.; Dall’Era, Marc A.; Vij, Anjali; Costello, Anthony J.; Chow, Ken; Corcoran, Niall M.; Rais-Bahrami, Soroush; Phares, Courtney; Scherr, Douglas S.; Flynn, Thomas; Karnes, R. Jeffrey; Koch, Michael; Dhondt, Courtney Rose; Nelson, Joel B.; McBride, Dawn; Cookson, Michael S.; Stratton, Kelly L.; Farriester, Stephen; Hemken, Erin; Stadler, Walter M.; Pera, Tuula; Banionyte, Deimante; Bianco, Fernando J., Jr.; Lopez, Isabel H.; Loeb, Stacy; Taneja, Samir S.; Byrne, Nataliya; Amling, Christopher L.; Martinez, Ann; Boileau, Luc; Gaylis, Franklin D.; Petkewicz, Jacqueline; Kirwen, Nicholas; Helfand, Brian T.; Xu, Jianfeng; Scholtens, Denise M.; Catalona, William J.; Witte, John S.; Urology, School of MedicineMen diagnosed with low-risk prostate cancer (PC) are increasingly electing active surveillance (AS) as their initial management strategy. While this may reduce the side effects of treatment for PC, many men on AS eventually convert to active treatment. PC is one of the most heritable cancers, and genetic factors that predispose to aggressive tumors may help distinguish men who are more likely to discontinue AS. To investigate this, we undertook a multi-institutional genome-wide association study (GWAS) of 5,222 PC patients and 1,139 other patients from replication cohorts, all of whom initially elected AS and were followed over time for the potential outcome of conversion from AS to active treatment. In the GWAS we detected 18 variants associated with conversion, 15 of which were not previously associated with PC risk. With a transcriptome-wide association study (TWAS), we found two genes associated with conversion (MAST3, p = 6.9 × 10−7 and GAB2, p = 2.0 × 10−6). Moreover, increasing values of a previously validated 269-variant genetic risk score (GRS) for PC was positively associated with conversion (e.g., comparing the highest to the two middle deciles gave a hazard ratio [HR] = 1.13; 95% confidence interval [CI] = 0.94–1.36); whereas decreasing values of a 36-variant GRS for prostate-specific antigen (PSA) levels were positively associated with conversion (e.g., comparing the lowest to the two middle deciles gave a HR = 1.25; 95% CI, 1.04–1.50). These results suggest that germline genetics may help inform and individualize the decision of AS—or the intensity of monitoring on AS—versus treatment for the initial management of patients with low-risk PC.Item Inhibition of β2-Microglobulin/Hemochromatosis Enhances Radiation Sensitivity by Induction of Iron Overload in Prostate Cancer Cells(Public Library of Science, 2013-07-10) Josson, Sajni; Matsuoka, Yasuhiro; Gururajan, Murali; Nomura, Takeo; Huang, Wen-Chin; Yang, Xiaojian; Lin, Jin-tai; Bridgman, Roger; Chu, Chia-Yi; Johnstone, Peter A.; Zayzafoon, Majd; Hu, Peizhen; Zhau, Haiyen; Berel, Dror; Rogatko, Andre; Chung, Leland W. K.; Radiation Oncology, School of MedicineBackground: Bone metastasis is the most lethal form of several cancers. The β2-microglobulin (β2-M)/hemochromatosis (HFE) complex plays an important role in cancer development and bone metastasis. We demonstrated previously that overexpression of β2-M in prostate, breast, lung and renal cancer leads to increased bone metastasis in mouse models. Therefore, we hypothesized that β2-M is a rational target to treat prostate cancer bone metastasis. Results: In this study, we demonstrate the role of β2-M and its binding partner, HFE, in modulating radiation sensitivity and chemo-sensitivity of prostate cancer. By genetic deletion of β2-M or HFE or using an anti-β2-M antibody (Ab), we demonstrate that prostate cancer cells are sensitive to radiation in vitro and in vivo. Inhibition of β2-M or HFE sensitized prostate cancer cells to radiation by increasing iron and reactive oxygen species and decreasing DNA repair and stress response proteins. Using xenograft mouse model, we demonstrate that anti-β2-M Ab sensitizes prostate cancer cells to radiation treatment. Additionally, anti-β2-M Ab was able to prevent tumor growth in an immunocompetent spontaneous prostate cancer mouse model. Since bone metastasis is lethal, we used a bone xenograft model to test the ability of anti-β2-M Ab and radiation to block tumor growth in the bone. Combination treatment significantly prevented tumor growth in the bone xenograft model by inhibiting β2-M and inducing iron overload. In addition to radiation sensitive effects, inhibition of β2-M sensitized prostate cancer cells to chemotherapeutic agents. Conclusion: Since prostate cancer bone metastatic patients have high β2-M in the tumor tissue and in the secreted form, targeting β2-M with anti-β2-M Ab is a promising therapeutic agent. Additionally, inhibition of β2-M sensitizes cancer cells to clinically used therapies such as radiation by inducing iron overload and decreasing DNA repair enzymes.Item Ketogenic diet alters the epigenetic and immune landscape of prostate cancer to overcome resistance to immune checkpoint blockade therapy(American Association for Cancer Research, 2024) Murphy, Sean; Rahmy, Sharif; Gan, Dailin; Liu, Guoqiang; Zhu, Yini; Manyak, Maxim; Duong, Loan; He, Jianping; Schofield, James H.; Schafer, Zachary T.; Li, Jun; Lu, Xuemin; Lu, Xin; Medicine, School of MedicineResistance to immune checkpoint blockade (ICB) therapy represents a formidable clinical challenge limiting the efficacy of immunotherapy. In particular, prostate cancer poses a challenge for ICB therapy due to its immunosuppressive features. A ketogenic diet (KD) has been reported to enhance response to ICB therapy in some other cancer models. However, adverse effects associated with continuous KD were also observed, demanding better mechanistic understanding and optimized regimens for using KD as an immunotherapy sensitizer. In this study, we established a series of ICB-resistant prostate cancer cell lines and developed a highly effective strategy of combining anti-PD1 and anti-CTLA4 antibodies with histone deacetylase inhibitor (HDACi) vorinostat, a cyclic KD (CKD), or dietary supplementation of the ketone body β-hydroxybutyrate (BHB), which is an endogenous HDACi. CKD and BHB supplementation each delayed prostate cancer tumor growth as monotherapy, and both BHB and adaptive immunity were required for the antitumor activity of CKD. Single-cell transcriptomic and proteomic profiling revealed that HDACi and ketogenesis enhanced ICB efficacy through both cancer cell-intrinsic mechanisms, including upregulation of MHC class I molecules, and -extrinsic mechanisms, such as CD8+ T-cell chemoattraction, M1/M2 macrophage rebalancing, monocyte differentiation toward antigen-presenting cells, and diminished neutrophil infiltration. Overall, these findings illuminate a potential clinical path of using HDACi and optimized KD regimens to enhance ICB therapy for prostate cancer. Significance: Optimized cyclic ketogenic diet and 1,3-butanediol supplementation regimens enhance the efficacy of immune checkpoint blockade in prostate cancer through epigenetic and immune modulations, providing dietary interventions to sensitize tumors to immunotherapy.Item Prediagnostic BMI trajectories in relation to pancreatic cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial(Wiley, 2022) Hoyt, Margaret; Song, Yiqing; Gao, Sujuan; O’Palka, Jacquelynn; Zhang, Jianjun; Epidemiology, School of Public HealthObjective: It remains elusive whether prediagnostic BMI trajectory is associated with pancreatic cancer. Methods: This study investigated this question among 145,489 participants who gave rise to 696 incident cases of pancreatic cancer over a median follow-up of 12 years in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. At baseline, participants were asked to recall their weight at ages 20, 50, and 55 to 74 years (at enrollment), as well as their height. Results: At age 50 years, people with obesity had a significantly increased risk of pancreatic cancer compared with those with a normal weight after adjustment for confounders (hazard ratio [95% CI]: 1.27 [1.01-1.60]). Individuals who had overweight at age 20 years experienced a marginally significant elevated risk of pancreatic cancer (hazard ratio [95% CI]: 1.22 [0.99-1.50]). Compared with individuals who maintained a steady normal weight during follow-up, no significantly altered risk of pancreatic cancer was observed for those whose weight status changed from normal weight to overweight, from normal weight to obesity, and from overweight to obesity. Conclusions: The present study revealed that prediagnostic adulthood BMI trajectory was not associated with pancreatic cancer risk, but overweight at young adulthood and obesity at middle adulthood may confer an elevated risk of this malignancy.Item Ras/ERK and PI3K/AKT signaling differentially regulate oncogenic ERG mediated transcription in prostate cells(PLOS, 2021-07-27) Strittmatter, Brady G.; Jerde, Travis J.; Hollenhorst, Peter C.; Pharmacology and Toxicology, School of MedicineThe TMPRSS2/ERG gene rearrangement occurs in 50% of prostate tumors and results in expression of the transcription factor ERG, which is normally silent in prostate cells. ERG expression promotes prostate tumor formation and luminal epithelial cell fates when combined with PI3K/AKT pathway activation, however the mechanism of synergy is not known. In contrast to luminal fates, expression of ERG alone in immortalized normal prostate epithelial cells promotes cell migration and epithelial to mesenchymal transition (EMT). Migration requires ERG serine 96 phosphorylation via endogenous Ras/ERK signaling. We found that a phosphomimetic mutant, S96E ERG, drove tumor formation and clonogenic survival without activated AKT. S96 was only phosphorylated on nuclear ERG, and differential recruitment of ERK to a subset of ERG-bound chromatin associated with ERG-activated, but not ERG-repressed genes. S96E did not alter ERG genomic binding, but caused a loss of ERG-mediated repression, EZH2 binding and H3K27 methylation. In contrast, AKT activation altered the ERG cistrome and promoted expression of luminal cell fate genes. These data suggest that, depending on AKT status, ERG can promote either luminal or EMT transcription programs, but ERG can promote tumorigenesis independent of these cell fates and tumorigenesis requires only the transcriptional activation function.Item Scoparone Exerts Anti-Tumor Activity against DU145 Prostate Cancer Cells via Inhibition of STAT3 Activity(Public Library of Science, 2013-11-15) Kim, Jeong-Kook; Kim, Joon-Young; Kim, Han-Jong; Park, Keun-Gyu; Harris, Robert A.; Cho, Won-Jea; Lee, Jae-Tae; Lee, In-Kyu; Biochemistry and Molecular Biology, School of MedicineScoparone, a natural compound isolated from Artemisia capillaris, has been used in Chinese herbal medicine to treat neonatal jaundice. Signal transducer and activator of transcription 3 (STAT3) contributes to the growth and survival of many human tumors. This study was undertaken to investigate the anti-tumor activity of scoparone against DU145 prostate cancer cells and to determine whether its effects are mediated by inhibition of STAT3 activity. Scoparone inhibited proliferation of DU145 cells via cell cycle arrest in G1 phase. Transient transfection assays showed that scoparone repressed both constitutive and IL-6-induced transcriptional activity of STAT3. Western blot and quantitative real-time PCR analyses demonstrated that scoparone suppressed the transcription of STAT3 target genes such as cyclin D1, c-Myc, survivin, Bcl-2, and Socs3. Consistent with this, scoparone decreased phosphorylation and nuclear accumulation of STAT3, but did not reduce phosphorylation of janus kinase 2 (JAK2) or Src, the major upstream kinases responsible for STAT3 activation. Moreover, transcriptional activity of a constitutively active mutant of STAT3 (STAT3C) was inhibited by scoparone, but not by AG490, a JAK2 inhibitor. Furthermore, scoparone treatment suppressed anchorage-independent growth in soft agar and tumor growth of DU145 xenografts in nude mice, concomitant with a reduction in STAT3 phosphorylation. Computational modeling suggested that scoparone might bind the SH2 domain of STAT3. Our findings suggest that scoparone elicits an anti-tumor effect against DU145 prostate cancer cells in part through inhibition of STAT3 activity.