Asterisk indicates 0

Asterisk indicates 0.05 (*) or 0.01 (**) by student’s unpaired test. STAT3 activities in breast carcinoma cells [5]. In pancreatic carcinoma cells, C12 also triggers apoptotic signaling and inhibits cell migration [6]. C12 decreases the expression of thymidylate synthase and enhances Dapagliflozin (BMS512148) the activity of chemotherapeutic agents, 5-fluorouracil (5-FU), Tomudex and Taxol in colorectal and prostate cancer cells. Recently, a derivative of C12, 3-oxo-12-phenyldodecanoyl-L-homoserine lactone, has been identified as another cancer cell growth inhibitor [8]. Comparative SAR analysis demonstrates that long acyl side chains with a 3-oxo substitution are essential Dapagliflozin (BMS512148) for C12s anti-cancer effect [8]. In light of its function of triggering tumor cell death, C12 displays promise as a cancer treatment. However, detailed apoptotic signaling of C12 remain unclear and whether C12 cytotoxicity is relevant to tumor growth has never been studied. Resistance toward apoptosis is a hallmark of most, perhaps all, types of human cancer [9, 10]. Bcl-2 proteins are the major regulators of apoptotic signaling pathways and can be classified into anti-apoptotic and pro-apoptotic groups. Anti-apoptotic Bcl-2 proteins such as Bcl-2 are considered to protect against mitochondrial outer membrane permeabilization (MOMP) during apoptosis, whereas pro-apoptotic Bcl-2 members such as Bax and Dapagliflozin (BMS512148) Bak promote MOMP [11, 12]. The expression of individual Bcl-2 proteins in different types of cancer has been used as an independent prognostic marker [10]. Studies in various human tumors showed that loss of Bax expression, or increased expression of Bcl-2, are associated with their resistance to chemotherapy [13C15]. Accordingly, one strategy for cancer therapy is to identify agonists that activate apoptotic pathway independent of Bcl-2 proteins in tumor cells [16C18]. As a lactone, C12 is known to be hydrolyzed into a carboxylic acid by the lactonase paraoxonase 2 (PON2), which belongs to a gene family (PON1, PON2 and PON3) with Ca2+-dependent lactonase and arylesterase activities [19, 20]. In murine airway epithelia, PON2 attenuates quorum sensing by inactivating C12 [21]. PON2 and PON3 also display anti-oxidant and anti-inflammatory functions [22C24]. The detailed mechanism by which PON2 exerts these effects remains unknown. Importantly, PON2 expression is markedly elevated in several human non-small cell lung Dapagliflozin (BMS512148) carcinoma (NSCLC) cell lines, which is associated with resistance to classical anticancer drugs like doxorubicin or cisplatin [23, 24]. In contrast, overexpression of PON2 Rabbit polyclonal to Dynamin-1.Dynamins represent one of the subfamilies of GTP-binding proteins.These proteins share considerable sequence similarity over the N-terminal portion of the molecule, which contains the GTPase domain.Dynamins are associated with microtubules. promotes C12-induced apoptosis in MEFs and HEK293T cells [25]. To gain insights into the mechanism of C12-evoked tumor cell apoptosis, we evaluated the cytotoxic effects of C12 on tumor cells and the inhibitory effects of C12 on tumor growth in a dose-dependent fashion(ACB) Cytotoxicity of C12 is affected by oncogenic transformation. C12’s effects on HBE cell viability (A) and caspase-3/7 activation (B) were examined. All data shown are mean standard deviation of 3 independent experiments. Asterisk indicates 0.05 (*) or 0.01 (**) by student’s unpaired test. (C) The inhibitory effects of C12 on the growth of LLC tumors were studied. Tumors were measured daily and tumor tissues were removed at the end of treatments. Data are shown as mean standard deviation of tumor volumes of 7 animals in either Dapagliflozin (BMS512148) vehicle control or C12-treated group. Asterisk indicates 0.05 (*) by student’s unpaired test. (D) Apoptotic cells in tumor sections were detected by immunofluorescence staining of activated caspase-3. Representative images of tumor sections are shown. Scale bar, 50 m. (E) The percentage of activated caspase-3 shown in (D) was quantified using ImageJ software (NIH). Data are mean standard deviation of three independent tumor sections. Asterisk indicates 0.01 (**) by student’s unpaired test. (F) Expression of activated caspase-3 in tumor tissues was analyzed by western blot. (G) The relative expression levels of.