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COMPOUND C INHIBITS OVARIAN CANCER PROGRESSION VIA PI3K/AKT/mTOR/NFκB PATHWAY

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abstract
Epithelial Ovarian cancer (OvCa) is the leading cause of death from gynecologic malignancies in the United States, with approximately 75% of patients diagnosed at late stages. High-grade serous cancer (HGSC) is the most common subtype (∼70%) and accounts for the majority of deaths. Despite aggressive surgical debulking and chemotherapy, recurrence of a chemo-resistant disease occurs in almost 80% of patients and is attributed to the propensity of OvCa cells to disseminate in the peritoneal cavity. Thus, to effectively treat advanced OvCa and drive durable remissions and even cures, therapies must potently induce tumor-selective cell death and target their molecular, phenotypic and metabolic adaptations. One such therapeutics is dorsomorphin, or Compound C. The goal of this study is to evaluate and validate the therapeutic efficacy of compound C in OvCa. We found that CC not only inhibited OvCa growth and invasiveness, but also inhibited the reciprocal crosstalk between OvCa cells and macrophages, and mesothelial monolayers. Mechanistic studies indicated that compound C exerted its effects on OvCa cells through inhibition of PI3K-AKT-NFκB; whereas in macrophages and mesothelial cells, CC inhibited cancer-cell-induced canonical NFκB activation. Real-time monitoring of OvCa cellular bioenergetics revealed that compound C inhibited ATP production, mitochondrial respiration, and non-mitochondrial oxygen consumption. In addition, compound C significantly decreased tumor burden of SKOV3 xenografts in nude mice and increased their sensitivity to cisplatin-treatment. Together, our findings highlight Compound C as a potent multi-faceted therapeutic in OvCa.
subject
NFkB
Ovarian Cancer
PI3K Pathway
Tumor Microenvironment
contributor
GHONEUM, ALIA (author)
Said, Neveen (committee chair)
Kridel, Steven (committee member)
Furdui, Cristina (committee member)
Lo, Hui-Wen (committee member)
Watabe, Kounosuke (committee member)
date
2021-06-03T08:35:55Z (accessioned)
2021 (issued)
degree
Cancer Biology (discipline)
2023-06-02 (liftdate)
embargo
2023-06-02 (terms)
identifier
http://hdl.handle.net/10339/98786 (uri)
language
en (iso)
publisher
Wake Forest University
title
COMPOUND C INHIBITS OVARIAN CANCER PROGRESSION VIA PI3K/AKT/mTOR/NFκB PATHWAY
type
Dissertation

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