In addition, overexpression of Beclin 1 has been shown to enhance the sensitivity the site of cervix and gastric cancer cells to chemotherapeutic drugs. On the contrary, he terozygous disruption of Beclin 1 in mice increases cellular proliferation and results in spontaneous malig nancies. Consistent with previous reports, in the current study, flowcytometry analysis and caspase 3 activity assay indicated that a greater Inhibitors,Modulators,Libraries in crease in apoptosis was observed in Beclin 1 transfected cells than the mock transfected cells. Controversially, Beclin 1 knockdown has been shown to promote apoptosis induced by doxorubicin in HepG2 cells. These reports there fore suggest that Beclin 1 may modulate apoptosis in cell specific and stimuli specific patterns.

It has been generally believed that Beclin 1 functions Inhibitors,Modulators,Libraries as a haploinsuf ficient tumor suppressor via autophagy activation. However, in the current study, we found that proteasome inhibitors activated autophagy in a Beclin 1 independent manner. In addition, suppression of autophagy both at the early stage and at the late stage had no obvious effects on cytotoxicity mediated by proteasome inhibitors. On the contrary, Beclin 1 overexpression enhanced respon siveness of ovarian cancer cells to proteasome inhibitors mediated cytotoxicity, indicating that Beclin 1 exerts autophagy independent tumor suppressive effect in ovar ian cancer cells upon exposure to proteasome inhibitors. Therefore, mechanisms underlying enhancing effects of Beclin 1 on chemosensitivity may Inhibitors,Modulators,Libraries be multifactorial, and the mechanisms by which Beclin 1 sensitizes ovarian caner cells to proteasome inhibition require further investigation.

Conclusions Proteasome inhibitors elicit PI3KC3 and Beclin 1 inde pendent autophagy in ovarian cancer cells. In addition, Beclin 1 sensitizes ovarian cancer cells to Inhibitors,Modulators,Libraries proteasome in hibition in autophagy independent manner. Background Reovirus is a small, non enveloped double stranded RNA virus, commonly isolated from the human respira tory or gastrointestinal tract. Infection is widespread, with 50 100% of adults showing seropositivity. However, reovirus is considered benign because most infections are either asymptomatic or result in only mild illness. Despite its lack of pathogenicity in humans, reo virus displays selective oncolytic activity against trans formed and malignant cells.

Initial mechanistic studies showed Inhibitors,Modulators,Libraries that transfection with elements of the Ras signalling pathway, including EGFR and its constitu tively active form v erbB, sos and mutated Ras itself, increased the sensitivity of cells to reovirus induced cell death. The kinase inhibitor Trichostatin A activated Ras signalling in these cells was subsequently found to inhibit the function of PKR, which in untransformed cells prevents viral protein translation. Thus, in Ras activated cells, dysfunctional PKR signalling allows reovirus replication to proceed and cell death ensues.