IU Indianapolis ScholarWorks :: Browsing by Author "Jerde, Travis J."

Browsing by Author "Jerde, Travis J."

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Anti-tumor activity and mechanistic characterization of APE1/Ref-1 inhibitors in bladder cancer
(American Association for Cancer Research, 2019-08-14) Fishel, Melissa L.; Xia, Hanyu; McGeown, Jack; McIlwain, David W.; Elbanna, May; Craft, Ariel A.; Kaimakliotis, Hristos Z.; Sandusky, George E.; Zhang, Chi; Pili, Roberto; Kelley, Mark R.; Jerde, Travis J.; Pharmacology and Toxicology, School of Medicine
Bladder cancer is the ninth most common cause of cancer-related deaths worldwide. Although cisplatin is used routinely in treating bladder cancer, refractory disease remains lethal for many patients. The recent addition of immunotherapy has improved patient outcomes; however, a large cohort of patients does not respond to these treatments. Therefore, identification of innovative molecular targets for bladder cancer is crucial. Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) is a multifunctional protein involved in both DNA repair and activation of transcription factors through reduction-oxidation (redox) regulation. High APE1/Ref-1 expression is associated with shorter patient survival time in many cancer types. In this study, we found high APE1/Ref-1 expression in human bladder cancer tissue relative to benign urothelium. Inhibition of APE1/Ref-1 redox signaling using APE1/Ref-1-specific inhibitors attenuates bladder cancer cell proliferation in monolayer, in three-dimensional cultures, and in vivo. This inhibition corresponds with an increase in apoptosis and decreased transcriptional activity of NF-κB and STAT3, transcription factors known to be regulated by APE1/Ref-1, resulting in decreased expression of downstream effectors survivin and Cyclin D1 in vitro and in vivo. We also demonstrate that in vitro treatment of bladder cancer cells with APE1/Ref-1 redox inhibitors in combination with standard-of-care chemotherapy cisplatin is more effective than cisplatin alone at inhibiting cell proliferation. Collectively, our data demonstrate that APE1/Ref-1 is a viable drug target for the treatment of bladder cancer, provide a mechanism of APE1/Ref-1 action in bladder cancer cells, and support the use of novel redox-selective APE1/Ref-1 inhibitors in clinical studies. SIGNIFICANCE: This work identifies a critical mechanism for APE1/Ref-1 in bladder cancer growth and provides compelling preclinical data using selective redox activity inhibitors of APE1/Ref-1 in vitro and in vivo.
The common parasite Toxoplasma gondii induces prostatic inflammation and microglandular hyperplasia in a mouse model
(Wiley, 2017-07) Colinot, Darrelle L.; Garbuz, Tamila; Bosland, Maarten C.; Wang, Liang; Rice, Susan E.; Sullivan, William J., Jr.; Arrizabalaga, Gustavo; Jerde, Travis J.; Pharmacology and Toxicology, School of Medicine
BACKGROUND: Inflammation is the most prevalent and widespread histological finding in the human prostate, and associates with the development and progression of benign prostatic hyperplasia and prostate cancer. Several factors have been hypothesized to cause inflammation, yet the role each may play in the etiology of prostatic inflammation remains unclear. This study examined the possibility that the common protozoan parasite Toxoplasma gondii induces prostatic inflammation and reactive hyperplasia in a mouse model. METHODS: Male mice were infected systemically with T. gondii parasites and prostatic inflammation was scored based on severity and focality of infiltrating leukocytes and epithelial hyperplasia. We characterized inflammatory cells with flow cytometry and the resulting epithelial proliferation with bromodeoxyuridine (BrdU) incorporation. RESULTS: We found that T. gondii infects the mouse prostate within the first 14 days of infection and can establish parasite cysts that persist for at least 60 days. T. gondii infection induces a substantial and chronic inflammatory reaction in the mouse prostate characterized by monocytic and lymphocytic inflammatory infiltrate. T. gondii-induced inflammation results in reactive hyperplasia, involving basal and luminal epithelial proliferation, and the exhibition of proliferative inflammatory microglandular hyperplasia in inflamed mouse prostates. CONCLUSIONS: This study identifies the common parasite T. gondii as a new trigger of prostatic inflammation, which we used to develop a novel mouse model of prostatic inflammation. This is the first report that T. gondii chronically encysts and induces chronic inflammation within the prostate of any species. Furthermore, T. gondii-induced prostatic inflammation persists and progresses without genetic manipulation in mice, offering a powerful new mouse model for the study of chronic prostatic inflammation and microglandular hyperplasia.
Coordinated induction of cell survival signaling in the inflamed microenvironment of the prostate
(Wiley, 2016-06) McIlwain, David W.; Zoetemelk, Marloes; Myers, Jason D.; Edwards, Marshé T.; Snider, Brandy M.; Jerde, Travis J.; Pharmacology and Toxicology, School of Medicine
PURPOSE: Both prostate cancer and benign prostatic hyperplasia are associated with inflammatory microenvironments. Inflammation is damaging to tissues, but it is unclear how the inflammatory microenvironment protects specialized epithelial cells that function to proliferate and repair the tissue. The objective of this study is to characterize the cell death and cell survival response of the prostatic epithelium in response to inflammation. METHODS: We assessed induction of cell death (TNF, TRAIL, TWEAK, FasL) and cell survival factors (IGFs, hedgehogs, IL-6, FGFs, and TGFs) in inflamed and control mouse prostates by ELISA. Cell death mechanisms were determined by immunoblotting and immunofluorescence for cleavage of caspases and TUNEL. Survival pathway activation was assessed by immunoblotting and immunofluorescence for Mcl-1, Bcl-2, Bcl-XL, and survivin. Autophagy was determined by immunoblotting and immunofluorescence for free and membrane associated light chain 3 (LC-3). RESULTS: Cleavage of all four caspases was significantly increased during the first 2 days of inflammation, and survival protein expression was substantially increased subsequently, maximizing at 3 days. By 5 days of inflammation, 50% of prostatic epithelial cells expressed survivin. Autophagy was also evident during the recovery phase (3 days). Finally, immunofluorescent staining of human specimens indicates strong activation of survival proteins juxtaposed to inflammation in inflamed prostate specimens. CONCLUSIONS: The prostate responds to deleterious inflammation with induction of cell survival mechanisms, most notably survivin and autophagy, demonstrating a coordinated induction of survival factors that protects and expands a specialized set of prostatic epithelial cells as part of the repair and recovery process during inflammation.
Expansion of prostate epithelial progenitor cells after inflammation of the mouse prostate
(American Physiological Society, 2015-06-15) Wang, Liang; Zoetemelk, Marloes; Chitteti, Brahmananda R.; Ratliff, Timothy L.; Myers, Jason D.; Srour, Edward F.; Broxmeyer, Hal; Jerde, Travis J.; Department of Pharmacology and Toxicology, IU School of Medicine
Prostatic inflammation is a nearly ubiquitous pathological feature observed in specimens from benign prostate hyperplasia and prostate cancer patients. The microenvironment of the inflamed prostate is highly reactive, and epithelial hyperplasia is a hallmark feature of inflamed prostates. How inflammation orchestrates epithelial proliferation as part of its repair and recovery action is not well understood. Here, we report that a novel epithelial progenitor cell population is induced to expand during inflammation. We used sphere culture assays, immunofluorescence, and flow cytometry to show that this population is increased in bacterially induced inflamed mouse prostates relative to naïve control prostates. We confirmed from previous reports that this population exclusively possesses the ability to regrow entire prostatic structures from single cell culture using renal grafts. In addition, putative progenitor cells harvested from inflamed animals have greater aggregation capacity than those isolated from naïve control prostates. Expansion of this critical cell population requires IL-1 signaling, as IL-1 receptor 1-null mice exhibit inflammation similar to wild-type inflamed animals but exhibit significantly reduced progenitor cell proliferation and hyperplasia. These data demonstrate that inflammation promotes hyperplasia in the mouse prostatic epithelium by inducing the expansion of a selected epithelial progenitor cell population in an IL-1 receptor-dependent manner. These findings may have significant impact on our understanding of how inflammation promotes proliferative diseases such as benign prostatic hyperplasia and prostate cancer, both of which depend on expansion of cells that exhibit a progenitor-like nature.
HUNK as an Immune Regulator of Triple Negative Breast Cancer
(2024-05) Ramos Solis, Nicole; Yeh, Elizabeth; Arrizabalaga, Gustavo; Fehrenbacher, Jill; Cook-Mills, Joan; Jerde, Travis J.
Triple-negative breast cancer (TNBC) is a subtype of breast cancer characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. Unlike other breast cancer types, TNBC tumors do not respond to endocrine therapy, and standardized treatment protocols for TNBC are currently unavailable. TNBC is recognized as a more metastatic, aggressive, and immunogenic subtype of breast cancer, rendering it to be more receptive to immunotherapy. Among the immune cell populations abundant in TNBC tumors, tumor-associated macrophages (TAMs) are particularly more prevalent and are particularly known to play a role in cancer metastasis. This work focuses on and investigates the involvement of the protein kinase HUNK in tumor immunity. With the use of gene expression analysis, such as NanoString's nCounter PanCancer Immune Profiling panel, we found that targeting HUNK is associated with alterations in the IL-4/IL-4R cytokine signaling pathway. Experimental analysis and work demonstrated that HUNK kinase activity regulates IL-4 production in mammary tumor cells, and this regulation is dependent on STAT3. Furthermore, in vivo, analysis shows that HUNK-dependent control of IL-4 secretion from tumor cells leads to the polarization of macrophages into an M2-like phenotype, and consequently, IL-4 induction promotes cancer metastasis and prompts macrophage's metastatic capacities. These findings underscore HUNK as a potential therapeutic target for mitigating TNBC metastasis by modulating the TAM population.
Identification of a Hypothalamic Neural System That Can Reduce Body Weight and Adipose Mass in Diet-Induced Obesity
(2024-11) Basu, Rashmita; Flak, Jonathan N.; Linnemann, Amelia K.; Witczak, Carol A.; Sheets, Patrick L.; Jerde, Travis J.
Dynamic hypothalamic circuits balance energy intake with expenditure to protect individuals from obesity. Lasting negative energy balance, however, triggers a compensatory decrease in energy expenditure, hindering progressive weight loss. While we understand some key players underlying energy balance, the detailed neural underpinnings remain unclear. Here I will delineate the functional efferent circuitry from the ventromedial hypothalamic nucleus (VMN) that facilitates weight loss and prevents rebound weight gain. VMN neurons have long been linked to a role in energy balance. Both vesicular communication by VMN steroidogenic factor 1 (SF1) neurons and pituitary adenylate cyclase activating peptide (PACAP) release from VMN neurons are essential for maintaining body weight and activating VMNSf1 neurons curbs diet-induced obesity without altering food intake. However, the exact pathway of this VMN signal is unclear because the VMN does not directly communicate with preganglionic sympathetic neurons, indicating signal transmission through an efferent node. Of the few brain sites they communicate with, VMNSf1 neurons sends the densest projections to the caudal preoptic area (POA) and the anterior bed nucleus of stria terminalis (BNST). Stimulating VMNPACAP axonal fibers in the caudal POA, but not anterior BNST, induced thermogenesis in brown and beige adipose tissues in both sexes of mice. To identify caudal POA populations in body weight regulation, I activated excitatory (glutamatergic) and inhibitory (GABAergic) caudal POA cells in diet-induced obese male mice and found that both glutamatergic and GABAergic caudal POA neurons can reduce diet-induced obesity through separate means. While there is intra-POA communication, my data supports efferent communication with separate downstream circuits by glutamate and GABA caudal POA cells in ameliorating diet-induced obesity. Because the POA and BNST are extremely complex regions with diverse functions, I then employed deep transfer learning to pinpoint obesity and diabetes risk-associated cell subsets in the POA and BNST. Using single nuclei RNA sequencing on >200,000 nuclei from both sexes of mice, I identified 6 specialized sets of caudal POA and BNST neuronal subtypes that increased in obese and glucose-intolerant mice on a high-fat diet. Targeting these newly identified pathways and neuron subtypes could lead to future obesity and diabetes therapeutics.
Inflammation impacts androgen receptor signaling in basal prostate stem cells through interleukin 1 receptor antagonist
(Springer Nature, 2024-10-25) Cooper, Paula O.; Yang, Jiang; Wang, Hsing-Hui; Broman, Meaghan M.; Jayasundara, Shyaman Madhawa; Sahoo, Subhransu Sekhar; Yan, Bingyu; Awdalkreem, Gada D.; Cresswell, Gregory M.; Wang, Liang; Goossens, Emery; Lanman, Nadia A.; Doerge, Rebecca W.; Zheng, Faye; Cheng, Liang; Alqahtani, Saeed; Crist, Scott A.; Braun, Robert E.; Kazemian, Majid; Jerde, Travis J.; Ratliff, Timothy L.; Microbiology and Immunology, School of Medicine
Chronic prostate inflammation in patients with benign prostate hyperplasia (BPH) correlates with the severity of symptoms. How inflammation contributes to prostate enlargement and/or BPH symptoms and the underlying mechanisms remain unclear. In this study, we utilize a unique transgenic mouse model that mimics chronic non-bacterial prostatitis in men and investigate the impact of inflammation on androgen receptor (AR) in basal prostate stem cells (bPSC) and their differentiation in vivo. We find that inflammation significantly enhances AR levels and activity in bPSC. More importantly, we identify interleukin 1 receptor antagonist (IL-1RA) as a crucial regulator of AR in bPSC during inflammation. IL-1RA is one of the top molecules upregulated by inflammation, and inhibiting IL-1RA reverses the enhanced AR activity in organoids derived from inflamed bPSC. Additionally, IL-1RA appears to activate AR by counteracting IL-1α's inhibitory effect. Furthermore, using a lineage tracing model, we observe that inflammation induces bPSC proliferation and differentiation into luminal cells even under castrate conditions, indicating that AR activation driven by inflammation is sufficient to promote bPSC proliferation and differentiation. Taken together, our study uncovers mechanisms through which inflammation modulates AR signaling in bPSC and induces bPSC luminal differentiation that may contribute to prostate hyperplasia.
Inflammation Impacts Androgen Receptor Signaling in Basal Prostate Stem Cells Through Interleukin 1 Receptor Antagonist
(Research Square, 2023-12-15) Cooper, Paula O.; Yang, Jiang; Wang, Hsing-Hui; Broman, Meaghan M.; Awdalkreem, Gada D.; Cresswell, Gregory M.; Wang, Liang; Goossens, Emery; Lanman, Nadia A.; Doerge, Rebecca W.; Zheng, Faye; Cheng, Liang; Crist, Scott A.; Braun, Robert E.; Jerde, Travis J.; Ratliff, Timothy L.; Pharmacology and Toxicology, School of Medicine
The majority of patients with benign prostate hyperplasia (BPH) exhibit chronic prostate inflammation and the extent of inflammation correlates with the severity of symptoms. How inflammation contributes to prostate enlargement and/or BPH symptoms and the underlying mechanisms are not clearly understood. We established a unique mouse model Prostate Ovalbumin Expressing Transgenic 3 (POET3) that mimics chronic non-bacterial prostatitis in men to study the role of inflammation in prostate hyperplasia. After the injection of ovalbumin peptide-specific T cells, POET3 prostates exhibited an influx of inflammatory cells and an increase in pro-inflammatory cytokines that led to epithelial and stromal hyperplasia. We have previously demonstrated with the POET3 model that inflammation expands the basal prostate stem cell (bPSC) population and promotes bPSC differentiation in organoid cultures. In this study, we investigated the mechanisms underlying the impact of inflammation on bPSC. We found that AR activity was enhanced in inflamed bPSC and was essential for bPSC differentiation in organoid cultures. Most importantly, we identified, for the first time, interleukin 1 receptor antagonist (IL-1RA) as a key regulator of AR in basal stem cells. IL-1RA was one of the top genes upregulated by inflammation and inhibition of IL-1RA abrogated the enhanced AR nuclear accumulation and activity in organoids derived from inflamed bPSC. The mirroring effects of IL-1RA recombinant protein and IL-1α neutralizing antibody suggest that IL-1RA may function by antagonizing IL-1α inhibition of AR expression. Furthermore, we established a lineage tracing model to follow bPSC during inflammation and under castrate conditions. We found that inflammation induced bPSC proliferation and differentiation into luminal cells even under castrate conditions, indicating that AR activation driven by inflammation in bPSC is sufficient for their proliferation and differentiation under androgen-deprived conditions. However, proliferation of the differentiated bPSC in the luminal layer significantly diminished with castration, suggesting inflammation may not maintain AR activity in stromal cells, as stromal cells deprived of androgen after castration could no longer provide paracrine growth factors essential for luminal proliferation. Taken together, we have discovered novel mechanisms through which inflammation modulates AR signaling in bPSC and induces bPSC luminal differentiation that contributes to prostate hyperplasia.
An Interaction with Ewing's Sarcoma Breakpoint Protein EWS Defines a Specific Oncogenic Mechanism of ETS Factors Rearranged in Prostate Cancer
(Elsevier, 2016-10-25) Kedage, Vivekananda; Selvaraj, Nagarathinam; Nicholas, Taylor R.; Budka, Justin A.; Plotnik, Joshua P.; Jerde, Travis J.; Hollenhorst, Peter C.; Department of Pharmacology and Toxicology, IU School of Medicine
More than 50% of prostate tumors have a chromosomal rearrangement resulting in aberrant expression of an oncogenic ETS family transcription factor. However, mechanisms that differentiate the function of oncogenic ETS factors expressed in prostate tumors from non-oncogenic ETS factors expressed in normal prostate are unknown. Here, we find that four oncogenic ETS (ERG, ETV1, ETV4, and ETV5), and no other ETS, interact with the Ewing's sarcoma breakpoint protein, EWS. This EWS interaction was necessary and sufficient for oncogenic ETS functions including gene activation, cell migration, clonogenic survival, and transformation. Significantly, the EWS interacting region of ERG has no homology with that of ETV1, ETV4, and ETV5. Therefore, this finding may explain how divergent ETS factors have a common oncogenic function. Strikingly, EWS is fused to various ETS factors by the chromosome translocations that cause Ewing's sarcoma. Therefore, these findings link oncogenic ETS function in both prostate cancer and Ewing's sarcoma.
Interleukin-driven insulin-like growth factor promotes prostatic inflammatory hyperplasia
(American Society for Pharmacology & Experimental Therapeutics (ASPET), 2014-12) Hahn, Alana M.; Myers, Jason D.; McFarland, Eliza K.; Lee, Sanghee; Jerde, Travis J.; Department of Pharmacology and Toxicology, IU School of Medicine
Prostatic inflammation is of considerable importance to urologic research because of its association with benign prostatic hyperplasia and prostate cancer. However, the mechanisms by which inflammation leads to proliferation and growth remain obscure. Here, we show that insulin-like growth factors (IGFs), previously known as critical developmental growth factors during prostate organogenesis, are induced by inflammation as part of the proliferative recovery to inflammation. Using genetic models and in vivo IGF receptor blockade, we demonstrate that the hyperplastic response to inflammation depends on interleukin-1-driven IGF signaling. We show that human prostatic hyperplasia is associated with IGF pathway activation specifically localized to foci of inflammation. This demonstrates that mechanisms of inflammation-induced epithelial proliferation and hyperplasia involve the induction of developmental growth factors, further establishing a link between inflammatory and developmental signals and providing a mechanistic basis for the management of proliferative diseases by IGF pathway modulation.

Browsing by Author "Jerde, Travis J."

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