Background:Ceramide is important for cellular signaling. Results: Increasing the expression of ceramide synthase 6 (CerS6) results in transcriptional activation of acid ceramidase independent of catalytic CerS6 activity. Conclusion: Modulation of a single member of the ceramide synthase family impacts on sphingolipid composition and ceramide metabolizing enzymes. Significance: Understanding how CerS impacts gene expression and signaling is important for the development of novel therapeutic approaches.
Monoclonal antibodies that block inhibitory immune checkpoint molecules and enhance antitumor responses show clinical promise in advanced solid tumors. Most of the preliminary evidence on therapeutic efficacy of immune checkpoint blockers comes from studies in melanoma, lung and renal cancer. To test the in vivo potential of programmed death –ligand 1 (PD-L1) blockade in ovarian cancer, we recently generated a new transplantable tumor model using human mucin 1 (MUC1)-expressing 2F8 cells. The MUC1 transgenic (MUC1.Tg) mice develop large number of intraperitoneal (IP) tumors following IP injection of 8x105 syngeneic 2F8 cells. The tumors are aggressive and display little T cell infiltration. Anti-PD-L1 antibody was administered IP every 2 weeks (200 μg/dose) for a total of 3 doses. Treatment was started 21 days post-tumor challenge, a time point which corresponds to late tumor stage. The anti-PD-L1 treatment led to substantial T cell infiltration within the tumor and significantly increased survival (p= 0.001) compared to isotype control- treated mice. When the same therapy was administered to wild type mice challenged with 2F8 tumors, no survival benefit was observed, despite the presence of high titer anti-MUC1 antibodies. However, earlier treatment (day 11) and higher frequency of IP injections restored the T cell responses and led to prolonged survival. Splenocyte profiling via Nanostring using probes for 511 immune genes revealed a treatment-induced immune gene signature consistent with increased T cell-mediated immunity. These findings strongly support further preclinical and clinical strategies exploring PD-L1 blockade in ovarian cancer.
Purpose-TRAIL, an endogenous protein involved in immunosurveillance and a novel drug in clinical trials, is of particular interest as a cancer therapeutic because it can induce apoptosis in cancer cells but not in normal cells. Since some cancers develop resistance to TRAIL, safe and effective methods of TRAIL sensitization are of great clinical interest. This study explores how chemotherapy and oxidative stress affect TRAIL sensitivity and expression of proteins in the apoptotic pathway.Materials and Methods-Sensitivity to TRAIL was assessed in viability assays. Apoptosis was measured by caspase-3/7 activity and/or nuclear condensation using Hoechst staining. Western blotting was used to determine cleavage, phosphorylation, or alterations in protein expression.Results-TRAIL reduced the viability of 5637 but not J82 and T24 bladder carcinoma cells. Chemotherapy with doxorubicin or cisplatin decreased the expression of the anti-apoptotic protein cFLIP S and increased caspase-8 cleavage, reversing TRAIL resistance in T24 cells. Specific targeting of cFLIP S by siRNA was insufficient for sensitization to TRAIL in T24 cells. However, chemotherapy-mediated TRAIL sensitization was mimicked by low concentrations of hydrogen peroxide, which resulted in phosphorylation of translation elongation factor 2 (EF2) and reduced expression of several short half-life, anti-apoptotic proteins including FLIP S , XIAP, and survivin.Conclusions-Induction of oxidative stress by low concentrations of hydrogen peroxide may reverse TRAIL resistance and warrants the further exploration of hydrogen peroxide as an adjuvant intravesical treatment to lower the apoptotic threshold of bladder cancer cells.
Activating mutations of Kras oncogene and deletions of Pten tumor suppressor gene play important roles in cancers of the female genital tract. We developed here new preclinical models for gynecologic cancers, using conditional (Cre-loxP) mice with floxed genetic alterations in Kras and Pten. The triple transgenic mice, briefly called MUC1KrasPten, express human MUC1 antigen as self and carry a silent oncogenic KrasG12D and Pten deletion mutation. Injection of Cre-encoding adenovirus (AdCre) in the ovarian bursa, oviduct or uterus activates the floxed mutations and initiates ovarian, oviductal, and endometrial cancer, respectively. Anatomical site-specific Cre-loxP recombination throughout the genital tract of MUC1KrasPten mice leads to MUC1 positive genital tract tumors, and the development of these tumors is influenced by the anatomical environment. Endometrioid histology was consistently displayed in all tumors of the murine genital tract (ovaries, oviducts, and uterus). Tumors showed increased expression of MUC1 glycoprotein and triggered de novo antibodies in tumor bearing hosts, mimicking the immunobiology seen in patients. In contrast to the ovarian and endometrial tumors, oviductal tumors showed higher nuclear grade. Survival for oviduct tumors was significantly lower than for endometrial tumors (p = 0.0015), yet similar to survival for ovarian cancer. Oviducts seem to favor the development of high grade tumors, providing preclinical evidence in support of the postulated role of fallopian tubes as the originating site for high grade human ovarian tumors.
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