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Browsing by Author "Yang-Hartwich, Yang"
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Item A Benzenesulfonamide-based Mitochondrial Uncoupler Induces Endoplasmic Reticulum Stress and Immunogenic Cell Death in Epithelial Ovarian Cancer(American Association for Cancer Research, 2021) Bi, Fangfang; Jiang, Ziyan; Park, Wonmin; Hartwich, Tobias M. P.; Ge, Zhiping; Chong, Kay Y.; Yang, Kevin; Morrison, Madeline J.; Kim, Dongin; Kim, Jaeyeon; Zhang, Wen; Kril, Liliia M.; Watt, David S.; Liu, Chunming; Yang-Hartwich, Yang; Biochemistry and Molecular Biology, School of MedicineEpithelial ovarian cancer (EOC) is a leading cause of death from gynecologic malignancies and requires new therapeutic strategies to improve clinical outcomes. EOCs metastasize in the abdominal cavity through dissemination in the peritoneal fluid and ascites, efficiently adapt to the nutrient-deprived microenvironment, and resist current chemotherapeutic agents. Accumulating evidence suggests that mitochondrial oxidative phosphorylation is critical for the adaptation of EOC cells to this otherwise hostile microenvironment. Although chemical mitochondrial uncouplers can impair mitochondrial functions and thereby target multiple, essential pathways for cancer cell proliferation, traditional mitochondria uncouplers often cause toxicity that precludes their clinical application. In this study, we demonstrated that a mitochondrial uncoupler, specifically 2,5-dichloro-N-(4-nitronaphthalen-1-yl)benzenesulfonamide, hereinafter named Y3, was an antineoplastic agent in ovarian cancer models. Y3 treatment activated AMP-activated protein kinase and resulted in the activation of endoplasmic reticulum stress sensors as well as growth inhibition and apoptosis in ovarian cancer cells in vitro. Y3 was well tolerated in vivo and effectively suppressed tumor progression in three mouse models of EOC, and Y3 also induced immunogenic cell death of cancer cells that involved the release of damage-associated molecular patterns and the activation of antitumor adaptive immune responses. These findings suggest that mitochondrial uncouplers hold promise in developing new anticancer therapies that delay tumor progression and protect ovarian cancer patients against relapse.Item Effect of exercise on peritoneal microenvironment and progression of ovarian cancer(e-Century Publishing, 2021-10-15) Morrisson, Madeline J.; Bi, Fangfang; Yang, Kevin; Cady, Sarah L.; Hartwich, Tobias M.P.; Cerchia, Alexandra P.; Li, Zhigui; Kim, Jaeyeon; Irwin, Melinda L.; Yang-Hartwich, Yang; Biochemistry and Molecular Biology, School of MedicineOvarian cancer is one of the deadliest gynecological malignancies and lacks treatments that do not significantly impact patient health-related quality of life. Exercise has been associated with reduced cancer risk and improved clinical outcomes; however the underlying molecular mechanisms are unknown. In this study, we utilized a treadmill-running exercise model to investigate the effects of exercise on high-grade serous ovarian carcinoma (HGSOC) progression and chemotherapy outcomes. We found that treadmill-running suppressed peritoneal colonization of tumors in a syngeneic mouse ovarian cancer model. Acute exercise stimulated the production of CCL2 and IL-15 in the peritoneal microenvironment while downregulating CCL22, VEGF, and CCL12. Using a co-culture model, we demonstrated the role of CCL2 in mediating the activity of peritoneal cells to inhibit cancer cell viability. We showed that the activation of M1 macrophages may contribute to the exercise-induced changes in the peritoneal microenvironment. We identified that chronic exercise modulates gene expression of intraperitoneal fat tissues related to lipid formation, thermogenesis, browning, and inflammation, which can contribute to inhibiting the colonization of metastatic ovarian cancer. Treadmill running also lowered blood urea nitrogen levels and reduced incidence of neutropenia and thrombocytopenia during chemotherapy in a mouse model, suggesting the potential beneficial effects of exercise in improving chemotherapy outcomes. Our data provided new insights into the acute and chronic effects of physical activity on ovarian cancer at the molecular and in vivo levels.Item Identification of miPEP133 as a novel tumor-suppressor microprotein encoded by miR-34a pri-miRNA(BMC, 2020-09-14) Kang, Min; Tang, Bo; Li, Jixi; Zhou, Ziyan; Liu, Kang; Wang, Rensheng; Jiang, Ziyan; Bi, Fangfang; Patrick, David; Kim, Dongin; Mitra, Anirban K.; Yang-Hartwich, Yang; Medical and Molecular Genetics, School of MedicineBackground Very few proteins encoded by the presumed non-coding RNA transcripts have been identified. Their cellular functions remain largely unknown. This study identifies the tumor-suppressor function of a novel microprotein encoded by the precursor of miR-34a. It consists of 133 amino acid residues, thereby named as miPEP133 (pri-microRNA encoded peptide 133). Methods We overexpressed miPEP133 in nasopharyngeal carcinoma (NPC), ovarian cancer and cervical cancer cell lines to determine its effects on cell growth, apoptosis, migration, or invasion. Its impact on tumor growth was evaluated in a xenograft NPC model. Its prognostic value was analyzed using NPC clinical samples. We also conducted western blot, immunoprecipitation, mass spectrometry, confocal microscopy and flow cytometry to determine the underlying mechanisms of miPEP133 function and regulation. Results miPEP133 was expressed in normal human colon, stomach, ovary, uterus and pharynx. It was downregulated in cancer cell lines and tumors. miPEP133 overexpression induced apoptosis in cancer cells and inhibited their migration and invasion. miPEP133 inhibited tumor growth in vivo. Low miPEP133 expression was an unfavorable prognostic marker associated with advanced metastatic NPC. Wild-type p53 but not mutant p53 induced miPEP133 expression. miPEP133 enhanced p53 transcriptional activation and miR-34a expression. miPEP133 localized in the mitochondria to interact with mitochondrial heat shock protein 70kD (HSPA9) and prevent HSPA9 from interacting with its binding partners, leading to the decrease of mitochondrial membrane potential and mitochondrial mass. Conclusion miPEP133 is a tumor suppressor localized in the mitochondria. It is a potential prognostic marker and therapeutic target for multiple types of cancers.Item In vivo modeling of metastatic human high-grade serous ovarian cancer in mice(PLOS, 2020-06-04) Kim, Olga; Park, Eun Young; Klinkebiel, David L.; Pack, Svetlana D.; Shin, Yong-Hyun; Abdullaev, Zied; Emerson, Robert E.; Coffey, Donna M.; Kwon, Sun Young; Creighton, Chad J.; Kwon, Sanghoon; Chang, Edmund C.; Chiang, Theodore; Yatsenko, Alexander N.; Chien, Jeremy; Cheon, Dong-Joo; Yang-Hartwich, Yang; Nakshatri, Harikrishna; Nephew, Kenneth P.; Behringer, Richard R.; Fernández, Facundo M.; Cho, Chi-Heum; Vanderhyden, Barbara; Drapkin, Ronny; Bast, Robert C., Jr.; Miller, Kathy D.; Karpf, Adam R.; Kim, Jaeyeon; Biochemistry and Molecular Biology, School of MedicineMetastasis is responsible for 90% of human cancer mortality, yet it remains a challenge to model human cancer metastasis in vivo. Here we describe mouse models of high-grade serous ovarian cancer, also known as high-grade serous carcinoma (HGSC), the most common and deadliest human ovarian cancer type. Mice genetically engineered to harbor Dicer1 and Pten inactivation and mutant p53 robustly replicate the peritoneal metastases of human HGSC with complete penetrance. Arising from the fallopian tube, tumors spread to the ovary and metastasize throughout the pelvic and peritoneal cavities, invariably inducing hemorrhagic ascites. Widespread and abundant peritoneal metastases ultimately cause mouse deaths (100%). Besides the phenotypic and histopathological similarities, mouse HGSCs also display marked chromosomal instability, impaired DNA repair, and chemosensitivity. Faithfully recapitulating the clinical metastases as well as molecular and genomic features of human HGSC, this murine model will be valuable for elucidating the mechanisms underlying the development and progression of metastatic ovarian cancer and also for evaluating potential therapies.Item Tumor microenvironment and immunology of ovarian cancer: 12th Biennial Rivkin Center Ovarian Cancer Research Symposium(BMJ, 2019) Mitra, Anirban K.; Yang-Hartwich, Yang; Medical and Molecular Genetics, School of MedicineThe 12th Biennial Ovarian Cancer Research Symposium organized by the Rivkin Center for Ovarian Cancer and the American Association for Cancer Research held on September 13–15, 2018 covered cutting edge and relevant research topics in ovarian cancer biology and therapy. Sessions included detection and prevention, genomics and molecular mechanisms, tumor microenvironment and immunology, novel therapeutics, and an education session. In this article we provide an overview of the key findings presented in the tumor microenvironment and immunology session.