Photoactivation of N-retinylidene-N-retinylethanolamine compromises autophagy in retinal pigmented epithelial cells.

As a part of the aging process, N-retinylidene-N-retinylethanolamine (A2E) accumulates in the retina to activate autophagy in retinal pigmented epithelial cells. However, the effect of A2E photoactivation on autophagy, which is more clinically relevant, still remains unclear. Here, we investigated the effect of blue light (BL)-activated A2E on autophagy in human retinal pigmented epithelial cells, ARPE-19. A significant increase in LC3-II protein was observed when BL was irradiated on ARPE-19 cells containing A2E. The mammalian target of rapamycin (mTOR) pathway was examined to verify whether autophagy was activated, but no change in AKT, mTOR, and 4EBP phosphorylation was observed. Transcription factor EB (TFEB) target gene expression, which is another pathway involved in autophagy, was also not altered by A2E and BL. However, intracellular p62 protein levels were significantly increased, which represented the inhibition of autophagic flux. To investigate the mechanism of the suppressed autophagic flux, the lysosomal state was observed. After BL irradiation, lysosomal damage was induced in A2E-treated ARPE-19 cells, and this phenomenon was prevented by treatment with the antioxidant, N-acetylcysteine. Our results suggest that A2E photoactivation compromises autophagy in ARPE-19 cells and that reactive oxygen species (ROS) play an important role in this process.

Plumbagin inhibits the proliferation of nasopharyngeal carcinoma 6-10B cells by upregulation of reactive oxygen species.

Plumbagin (PLB) is the primary component of the traditional Chinese medicine Baihua Dan, and possesses anti-infection and anticancer effects, with the ability to enhance the sensitivity of tumor cells to radiation therapy. However, the anticancer effect of PLB on nasopharyngeal carcinoma and the underlying mechanisms remain unclear. In this study, we investigated the anticancer effects of PLB on nasopharyngeal carcinoma 6-10B cells and clarified its molecular mechanisms in vitro. The results showed that PLB was effective against 6-10B cells proliferation in a dose-dependent manner by inducing G2/M phase cell cycle arrest. Furthermore, our data showed that PLB induced reactive oxygen species accumulation, which inhibited the GSK3ß/STAT3 pathway and arrested the G2/M phase. Therefore, our results provided new insight into the mechanism of the antitumor effects of PLB, supporting PLB as a prospective therapeutic drug in nasopharyngeal carcinoma by modulating intracellular redox balance.

Inhibition of disheveled-2 resensitizes cisplatin-resistant lung cancer cells through down-regulating Wnt/ß-catenin signaling.

Cisplatin (CDDP) is currently recommended as the front-line chemotherapeutic agent for lung cancer. However, the resistance to cisplatin is widespread in patients with advanced lung cancer, and the molecular mechanism of such resistance remains incompletely understood. Disheveled (DVL), a key mediator of Wnt/ß-catenin, has been linked to cancer progression, while the role of DVL in cancer drug resistance is not clear. Here, we found that DVL2 was over-expressed in cisplatin-resistant human lung cancer cells A549/CDDP compared to the parental A549 cells. Inhibition of DVL2 by its inhibitor (3289-8625) or shDVL2 resensitized A549/CDDP cells to cisplatin. In addition, over-expression of DVL2 in A549 cells increased the protein levels of BCRP, MRP4, and Survivin, which are known to be associated with chemoresistance, while inhibition of DVL2 in A549/CDDP cells decreased these protein levels, and reduced the accumulation and nuclear translocation of ß-catenin. In addition, shß-catenin abolished the DVL2-induced the expression of BCRP, MRP4, and Survivin. Furthermore, our data showed that GSK3ß/ß-catenin signals were aberrantly activated by DVL2, and inactivation of GSK3ß reversed the shDVL2-induced down-regulation of ß-catenin. Taken together, these results suggested that inhibition of DVL2 can sensitize cisplatin-resistant lung cancer cells through down-regulating Wnt/ß-catenin signaling and inhibiting BCRP, MRP4, and Survivin expression. It promises a new strategy to chemosensitize cisplatin-induced cytotoxicity in lung cancer.

CXCR7 expression in nasopharyngeal carcinoma tissues correlates with disease severity.

The chemokine CXCL12 and its receptors, CXCR4 and CXCR7, are important contributors to the pathogenesis of multiple types of tumors. CXCL12/CXCR4 was previously demonstrated to be upregulated in nasopharyngeal carcinoma (NPC) tissues, but the status of CXCR7 in NPC remains unknown. Here, 62 nasopharyngeal carcinoma specimens were obtained from patients who received rhinitis biopsy in our hospital in 2012 and 2013. Another 30 samples were collected from patients with nasopharyngitis who did not have NPC, to serve as a control group. Expression of CXCR7 protein and mRNA in NPC and normal tissues was detected by immunohistochemistry and quantitative real-time polymerase chain reaction, respectively. CXCR7 protein was detected in just 7.1% (2/30) of normal nasopharyngeal samples, but 61.3% (38/62) of tumor tissues (P<0.05). The staining patterns (proportion of stained cells/sample as well as staining intensity) were correlated with lymph node metastasis, TNM staging, and disease severity (P<0.01). Thus, CXCR7 may promote disease progression in nasopharyngeal carcinoma, and may be useful as a predictor of metastasis and prognosis.