Browsing by Subject "cell survival"

Now showing 1 - 5 of 5
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    DMAPT AS A POTENTIAL RADIOSENSITIZER FOR PANCREATIC CANCER CELLS
    (Office of the Vice Chancellor for Research, 2012-04-13) Gill, Kiran; Mendonca, Marc
    Pancreatic cancer is the fourth leading cause of cancer-related death in the United States with an estimated 37, 390 deaths expected to occur in 2012. The prognosis is very poor due to the recurrence and metastasis of the cancer with a 6% five-year survival rate for all stages combined. This study examined the effectiveness of dimethylamino-parthenolide (DMAPT) as a radiosensitizer to the human pancreatic cancer PaCa2 cell line. It is hypothe-sized that DMAPT, a bioavailable drug derived from parthenolide, will inhibit the activation of NF-κB and enhance radiation-induced cell killing of PaCa2 cells. NF-κB is a transcription factor that promotes cell survival, tumor pro-gression, and angiogenesis and reduces susceptibility to apoptosis. The re-sults show that DMAPT was toxic to the PaCa2 cell line. As a result, DMAPT suppressed cell growth and increased the doubling time of PaCa2 cells. The combination of 4μM DMAPT and radiation decreased cell survival. The PaCa2 cell line is radiosensitized by DMAPT but further investigation is required to determine the mechanism through which DMAPT works.
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    The microenvironment reprograms circuits in tumor cells
    (Informa UK (Taylor & Francis), 2015-01) Cai, Qingchun; Xu, Yan; Department of Obstetrics & Gynecology, IU School of Medicine
    In the course of multistep oncogenesis, initially normal cells acquire several new functions that render them malignant. We have recently demonstrated that the peritoneal microenvironment promotes resistance to anoikis in ovarian cancer cells by reprogramming SRC/AKT/ERK signaling and metabolism. These findings have prognostic and therapeutic implications.
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    Novel Roles of p21 in Apoptosis During Beta-Cell Stress in Diabetes
    (2014) Hernández-Carretero, Angelina M.; Fueger, Patrick T.; Sturek, Michael Stephen; Wek, Ronald C.; Evans-Molina, Carmella; Elmendorf, Jeffrey S.
    Type 2 diabetes manifests from peripheral insulin resistance and a loss of functional beta cell mass due to decreased beta cell function, survival, and/or proliferation. Beta cell stressors impair each of these factors by activating stress response mechanisms, including endoplasmic reticulum (ER) stress. The glucolipotoxic environment of the diabetic milieu also activates a stress response in beta cells, resulting in death and decreased survival. Whereas the cell cycle machinery (comprised of cyclins, kinases, and inhibitors) regulates proliferation, its involvement during beta cell stress in the development of diabetes is not well understood. Interestingly, in a screen of multiple cell cycle inhibitors, p21 was dramatically upregulated in INS-1-derived 832/13 cells and rodent islets by two independent pharmacologic inducers of beta cell stress - dexamethasone and thapsigargin. In addition, glucolipotoxic stress mimicking the diabetic milieu also induced p21. To further investigate p21’s role in the beta cell, p21 was adenovirally overexpressed in 832/13 cells and rat islets. As expected given p21’s role as a cell cycle inhibitor, p21 overexpression decreased [3H]-thymidine incorporation and blocked the G1/S and G2/M transitions as quantified by flow cytometry. Interestingly, p21 overexpression activated apoptosis, demonstrated by increased annexin- and propidium iodide-double-positive cells and cleaved caspase-3 protein. p21-mediated caspase-3 cleavage was inhibited by either overexpression of the anti-apoptotic mitochondrial protein Bcl-2 or siRNA-mediated suppression of the pro-apoptotic proteins Bax and Bak. Therefore, the intrinsic apoptotic pathway is central for p21-mediated cell death. Like glucolipotoxicity, p21 overexpression inhibited the insulin cell survival signaling pathway while also impairing glucose-stimulated insulin secretion, an index of beta cell function. Under both conditions, phosphorylation of insulin receptor substrate-1, Akt, and Forkhead box protein-O1 was reduced. p21 overexpression increased Bim and c-Jun N-terminal Kinase, however, siRNA-mediated reduction or inhibition of either protein, respectively, did not alter p21-mediated cell death. Importantly, islets of p21-knockout mice treated with the ER stress inducer thapsigargin displayed a blunted apoptotic response. In summary, our findings indicate that p21 decreases proliferation, activates apoptosis, and impairs beta cell function, thus being a potential target to inhibit for the protection of functional beta cell mass.
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    Post-Injury Treatment of 7,8-Dihydroxyflavone Promotes Neurogenesis in the Hippocampus of the Adult Mouse
    (Mary Ann Liebert, 2016-11-15) Zhao, Shu; Yu, Alex; Wang, Xiaoting; Gao, Xiang; Chen, Jinhui; Neurological Surgery, School of Medicine
    Traumatic brain injury (TBI) at the moderate level of impact induces massive cell death and results in extensive dendrite degeneration in the brain, leading to persistent cognitive, sensory, and motor dysfunction. Our previous reports have shown that adult-born immature granular neurons in the dentate gyrus are the most vulnerable cell type in the hippocampus after receiving a moderate TBI with a controlled cortical impact (CCI) device. There is no effective approach to prevent immature neuron death or degeneration following TBI. Our recent study found that pretreatment of 7,8-dihydroxyflavone (DHF), a small molecule imitating brain-derived neurotrophic factor, protected immature neurons in the hippocampus from death following TBI. In the present study, we systemically treated moderate CCI-TBI mice or sham surgery mice with DHF once a day for 2 weeks via intraperitoneal injection, and then assessed the immature neurons in the hippocampus the 2nd day after the last DHF injection. We found that post-injury treatment of DHF for 2 weeks not only increased the number of adult-born immature neurons in the hippocampus, but also promoted their dendrite arborization in the injured brain following TBI. Thus, DHF may be a promising compound that can promote neurogenesis and enhance immature neuron development following TBI.
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    Tissue transglutaminase protects epithelial ovarian cancer cells from cisplatin-induced apoptosis by promoting cell survival signaling
    (Oxford University Press, 2008-10) Cao, Liyun; Petrusca, Daniela N.; Satpathy, Minati; Nakshatri, Harikrishna; Petrache, Irina; Matei, Daniela
    Tissue transglutaminase (TG2), an enzyme involved in protein cross-linking and overexpressed in ovarian tumors, has antiapoptotic effects in cancer cells and may play a role in response to chemotherapy. In this study, we investigated the role of TG2 in the sensitivity of ovarian cancer cells to cisplatin. By using stable knockdown and overexpression strategies, we demonstrate that the level of expression of TG2 regulates apoptosis induced by cisplatin in SKOV3 and OV-90 ovarian cancer cells. Interestingly, not only TG2 knockdown but also a TG2 enzymatic inhibitor (KCC009) sensitized SKOV3 cells to cisplatin. To understand the mechanism by which TG2 exerts its antiapoptotic role, we examined the effects of protein kinase B (Akt) and nuclear factor-kappa B (NF-κB), two survival pathways commonly involved in development of drug resistance. Overexpression of the constitutively active p65 subunit of NF-κB, but not constitutively active Akt, rescued cells with diminished TG2 expression from cisplatin-induced apoptosis. This implicates activation of NF-κB as the main cisplatin resistance mechanism downstream of TG2. Indeed, NF-κB activity is decreased and the level of the inhibitory subunit IκBα is increased in ovarian cancer cells engineered to express diminished levels of TG2 or treated with the enzymatic inhibitor, KCC009. Our data show that TG2 prevents apoptosis induced by cisplatin by activating the NF-κB survival pathway in ovarian cancer cells.