Browsing by Author "Kim, Dongin"

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    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 Medicine
    Epithelial 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.
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    Correction: Identification of miPEP133 as a novel tumor-suppressor microprotein encoded by miR-34a pri-miRNA
    (Springer Nature, 2024-09-12) Kang, Min; Tang, Bo; Li, Jixi; Zhou, Ziyan; Liu, Kang; Wang, Rensheng; Jiang, Ziyan; Bi, Fangfang; Patrick, David; Kim, Dongin; Mitra, Anirban K.; Hartwich, Yang Yang; Medicine, School of Medicine
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    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 Medicine
    Background 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.