Browsing by Author "Liu, Jingyuan"

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    Effective targeting of the survivin dimerization interface with small molecule inhibitors
    (AACR, 2016-01) Qi, Jing; Dong, Zizheng; Liu, Jianguo; Peery, Robert C.; Zhang, Shaobo; Liu, Jingyuan; Zhang, Jian-Ting; Department of Pathology and Laboratory Medicine, IU School of Medicine
    Many oncoproteins are considered undruggable because they lack enzymatic activities. In this study, we present a small-molecule–based anticancer agent that acts by inhibiting dimerization of the oncoprotein survivin, thereby promoting its degradation along with spontaneous apoptosis in cancer cells. Through a combination of computational analysis of the dimerization interface and in silico screening, we identified one compound that induced proteasome-dependent survivin degradation. Analysis of a set of structural analogues led us to identify a lead compound (LQZ-7F), which was effective in blocking the survival of multiple cancer cell lines in a low micromolar concentration range. LQZ-7F induced proteasome-dependent survivin degradation, mitotic arrest, and apoptosis, and it blocked the growth of human tumors in mouse xenograft assays. In addition to providing preclinical proof of concept for a survivin-targeting anticancer agent, our work offers novel in silico screening strategies to therapeutically target homodimeric oncogenic proteins considered undruggable.
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    Utilization of Proton Pump Inhibitors in Combination Regimen for Breast Cancer Treatment by Targeting Fatty Acid Synthase
    (2018-11) Wang, Chao; Zhang, Jian-Ting; Pollok, Karen E.; Liu, Jingyuan; Safa, Ahmad
    Fatty acid synthase (FASN) over-expression has been associated with poor prognosis and recurrence in cancer patients. In addition, it has also been found that overexpression of FASN causes resistance to DNA-damaging treatments by up-regulating the non-homologous end joining (NHEJ) repair of DNA double-strand break. Proton pump inhibitors (PPIs), were originally designed to decrease gastric acid production by binding irreversibly with gastric hydrogen potassium ATPase. PPIs have recently been reported to reduce drug resistance in cancer cells when used in combination with other chemotherapeutics, although the mechanism of resistance reduction is uncertain. In our lab, previous investigation showed that PPIs decreased FASN thioesterase (TE) domain activity and cancer cell proliferation in a dose-dependent manner. In this study, I tested the hypothesis that PPIs sensitize breast cancer cells to doxorubicin and ionizing radiation (IR) treatments by inhibiting FASN. When administered to breast cancer cells as single-agent, lansoprazole exhibited the highest potency in inhibiting both FASN activity and breast cancer cell proliferation, among four PPIs tested. In addition, treatment of breast cancer cells with lansoprazole decreased the mRNA and protein levels of poly (ADP-ribose) polymerase-1 (PARP-1) and NHEJ activity, accompanied by elevated γ-H2AX expression. Following a 3-day treatment with lansoprazole, a dose-dependent disruption in cell cycle disruption and increased apoptosis were also detected. Combination of lansoprazole with either doxorubicin or IR caused profoundly higher levels of DNA damage accumulation than doxorubicin or IR treatment alone, suggesting synergistic effects. Taken together, our observations suggest that PPIs synergistically suppress breast cancer cells in combination with DNA damaging treatments by inhibiting FASN. These findings may provide a potential route to overcome resistance to DNA-damaging chemo/radiation treatments in refractory breast cancers.