SOX2 upregulates side population cells and enhances their chemoresistant ability by transactivating ABCC1 expression contributing to intrinsic resistance to paclitaxel in melanoma.

Paclitaxel is the last choice for the treatment of advanced melanoma as a second-line chemotherapeutic agent, but there are still many cases of intrinsic resistance to paclitaxel in melanoma and the reasons that cause paclitaxel resistance remain unclear. Here, we identified that high expression of SRY-box transcription factor 2 (SOX2) and high ratio of side population (SP) cells reduced the sensitivity to paclitaxel in melanoma cells. The knockout and the induction of SOX2 completely depleted and significantly upregulated the ratios of melanoma SP cells, respectively. These data suggest that SOX2, a pluripotent transcription factor for inducing cancer stem cells in melanoma, is also sufficient and necessary for the induction of melanoma SP cells. ATP-binding cassette (ABC) subfamily C member 1 (ABCC1) is one of ABC transporters which causes SP cells to be resistance to chemotherapeutic agents by efficiently pumping drugs out of cells. The knockout and the induction of ABCC1 significantly increased and decreased the sensitivity of melanoma cells to paclitaxel. High expression of ABCC1 was identified in melanoma cell lines with high expression of SOX2 and in their SP cells. SOX2 was identified to induce ABCC1 transcription. Taken together, SOX2 upregulates SP cells and enhances their chemoresistant ability by increasing ABCC1 expression, which contributes to intrinsic resistance to paclitaxel in melanoma. Our findings will lead to new insights into melanoma biology and therapy resistance, and eventually to new therapeutic targets.

The antagonism of aluminum against fluoride-induced oxidative stress and c-Fos overexpression in rat testes.

Sodium fluoride (NaF) has been found to interfere with the reproductive system of animals. However, the cellular mechanisms underlying the reproductive toxicity of fluoride are unclear. The present study aims to define a possible mechanism of NaF-induced reproductive toxicity with respect to mineral, oxidative stress and c-Fos expression and the role of aluminum (Al) in intervening the toxic effect of NaF on rat testes. Fifty-six male Wistar rats were treated with normal saline, 1.0, 2.0, and 3.0 mg NaF/kg body weight (bw)/day, and each NaF concentration plus Al ion (0.1 mg Al(3+)/kg bw/day). After 90 days, no significant changes in the contents of Fe and Cu were observed in any of the NaF-treated groups compared with those of the control group. There were, however, significant decreases in the contents of Ca in the 1.0 mg NaF group, Zn in all NaF-treated groups and Mg in the 3.0 mg NaF group. The levels of malondialdehyde (MDA) in the 1.0 mg NaF group and hydrogen peroxide (H2O2) in the 2.0 mg NaF group significantly increased, whereas the activity of nitric oxide synthase (NOS) significantly decreased in the 1.0 mg NaF group. Meanwhile, the protein expression of c-Fos increased significantly in the 1.0 and 2.0 mg NaF groups compared with the control group. Conversely, these changes were partially attenuated in rats simultaneously administered Al. The present study suggested that NaF could decrease the contents of Ca, Fe and Mg and enhance oxidative stress leading to c-Fos overexpression, and some deleterious effects were more prominent at lower NaF intake. Furthermore, Al within the research concentration could minimize reproductive toxicity caused by fluoride.

CADM1 inhibits ovarian cancer cell proliferation and migration by potentially regulating the PI3K/Akt/mTOR pathway.

Previous studies have shown that cell adhesion molecule 1 (CADM1), an immunoglobulin superfamily member, is frequently inactivated but functions as a tumor suppressor in many solid tumors. However, the characterization of CADM1 expression in ovarian cancer cells and the mechanisms of its tumor suppressor function are not fully understood. We generated ovarian cancer cell lines in which CADM1 was stably upregulated or downregulated. CADM1 expression was significantly decreased in ovarian cancer tissue and cells lines. Functionally, knockdown of CADM1 promoted the growth, migration and invasion of ovarian cancer cells. Conversely, further experimental evidence indicated that overexpression of CADM1 inhibited the migration and invasion of ovarian cancer cells potentially through inhibition of the PI3K/Akt/mTOR signaling pathway by regulating upstream regulators (LXR/RXR, IGF1, IFI44L and C4BPA) and downstream effectors (APP, EDN1, TGFBI and Rap1A). In conclusion, CADM1 inhibits ovarian cancer cell proliferation and migration by potentially regulating the PI3K/Akt/mTOR signaling pathway. CADM1 could be a potential therapeutic target for ovarian cancer.

Downregulating SynCAM and MPP6 expression is associated with ovarian cancer progression.

Synaptic cell adhesion molecules (SynCAMs) are single transmembrane proteins that belong to the immunoglobulin superfamily of cell adhesion molecules. In the present study, a decrease in SynCAM levels in ovarian tumor tissues compared with normal tissues is reported; the downregulation was accompanied by the grade malignancy. The observations suggested that SynCAM may be essential for important novel functions in ovarian cancer. Further experiments showed that low SynCAM expression inhibited membrane palmitoylated protein 6 (MPP6) expression, a member of the palmitoylated membrane protein subfamily of peripheral membrane-associated guanylate kinases. In addition, low levels of MPP6 in ovarian tumor tissues correlated with shorter patient survival. A SynCAM-regulated pathway may provide molecular targets for the treatment of ovarian cancer and novel biomarkers to be used in clinical diagnosis.