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The aberrant activation of PI3K/Akt/mTOR signaling pathway plays an important role in the oncogenesis, prognosis and chemotherapy resistance of neuroblastoma. However, NVP-BEZ235, a potent dual PI3K and mTOR inhibitor have not shown beneficial effects on neuroblastoma especially in terms of apoptosis induction as a single agent. We therefore attempted to explore an effective combination regimen to enhance the anticancer activity of NVP-BEZ235. Interestingly, we found that oridonin, a natural biologically active compound extracted from the Chinese medicinal herb Rabdosia rubescens, combined with NVP-BEZ235 markedly induced apoptosis of neuroblastoma cells. Notably, the synergistic activation of the apoptotic pathway was accompanied with enhanced autophagy as evidenced by significant decreased p62 expression as well as upregulated conversion of LC3-II. Suppression of the Beclin-1, a core component of the autophagy machinery, by means of shRNA resulted in diminished synergistic antitumor effect. Furthermore, the co-treatment with oridonin and NVP-BEZ235 was also much more effective than either agent alone in inhibiting the growth of neuroblastoma xenografts and in inducing tumor cells apoptosis. Taken together, our results suggest that the combination of NVP-BEZ235 and oridonin is a novel and potential strategy for neuroblastoma therapy.

Gastric cancer cell are not particularly sensitive to Ara-C, a deoxycytidine analog that affects DNA synthesis. In the present study, AGS and MKN-45 gastric cancer cell lines were treated with Ara-C to determine its role in cell prolife-ration and apoptosis. The antiproliferative effect of Ara-C was assessed using the Cell Counting kit-8. Gelatinase zymography was utilized to detect the activity of MMP-2 and MMP-9, and an in vitro invasion assay was performed. Using RT-PCR, CD-147, MMP-2 and MPP-9 mRNA levels were assessed in AGS cells with various doses of Ara-C treatment. CD-147, MMP-2 and MMP-9 protein levels were analysed in Ara-C‑treated AGS and MKN-45 cells. AGS cells were treated with or without U-0126 or siRNA-CD147 and/or Ara-C for 24 h, and an in vitro invasion assay was performed. Although low-dose Ara-C had no obvious effect on cell proliferation, it upregulated the expression of MMP-2, MMP-9 and CD-147 and ERK activation. Low-dose Ara-C increased gastric cancer cell invasion. U-0126 and siRNA-CD-147 inhibited the induction of Ara-C in gastric cancer cell invasion. Therefore, Ara-C enhances the invasiveness of gastric cancer cells by expression of CD-147 /MMP-2 and MMP-9 via the ERK signaling pathway. The results are therefore useful in the prevention of Ara-C collateral damage associated with standard, conventional protocols of chemotherapy administration.

The expression of miR-145 with tumor suppressor function is decreased in lung cancer cells. Epidermal growth factor receptor (EGFR) signaling pathway is abnormally activated in lung cancer cells. It is not clear whether the EGFR signaling pathway is involved in the regulation of miR-145 expression in lung cancer. In the present study, we found that the reduction of miR-145 was associated with EGFR abnormal activation in lung cancer cells. AG1478, an inhibitor of EGFR, may restore the expression of miR-145, indicating that EGFR activation is involved in the downregulation of miR-145 in lung cancer cells. Then, the application of STAT3, AKT and ERK1/2 inhibitors and siRNA against these signaling molecules indicated that ERK1/2 or AKT instead of STAT3 was involved in the process of miR-145 downregulation by EGFR. It was confirmed that AKT through activation of the ERK1/2 signaling molecules mediated the effect of EGFR on miR-145. Furthermore, we found that EGFR downregulated miR-145 through ERK1/2 in lung cancer cells. These findings establish EGFR and miR-145 links in lung cancer cells and therefore contribute to a better understanding of the role of EGFR in lung cancer cells, and provide clues for in-depth study of miR-145 expression and a possible direction for the further increase of miR-145 in lung cancer cells.

The transcription factor Ikaros was originally found to function as a key regulator of lymphocyte differentiation. In this study, we provide the first evidence that Ikaros is expressed at higher levels in ovarian cancer tissues compared with normal ovarian tissues and is significantly associated with high FIGO stage and low differentiation state in ovarian serous adenocarcinoma. To this end, we transfected IK1 (full length of Ikaros) into the SKOV3 ovarian cancer cell line and examined cell biological behaviors including proliferation, migration and invasion. We found that overexpression of IK1 inhibited cell proliferation by inducing G1 arrest, accompanied by the upregulation of P27 and P21 and downregulation of cyclin D1 and D2. On the other hand, IK1 increased the migration and invasion of ovarian cancer cells, as assessed by scratch-wound assay, transwell migration assay, and invasion assay. Overexpression of IK1 significantly increased Slug but not Snail1 expression at both mRNA and protein levels. It also downregulated and upregulated E-cadherin and MMP-2, two target genes of Slug involved in migration, respectively. Furthermore, knocking down Slug abrogated IK1-mediated increase in migration and invasion. These data suggest that Slug plays an important role in IK1-induced migration and invasion. In conclusion, we show for the first time that IK1 plays a dual role in the proliferation, migration and invasion of ovarian cancer cells, providing new insights into their metastasis.

We recently demonstrated that oridonin could induce apoptosis and senescence of colon cancer cells in vitro and in vivo. However, the underlying mechanism remains unknown. In this study, the involvement of reactive oxygen species in oridonin-induced cell death and senescence was investigated in colon adenocarcinoma-derived SW1116 cells. Oridonin increased intracellular hydrogen peroxide levels and reduced the glutathione content in a dose-dependent manner. N-acetylcysteine, a reactive oxygen species scavenger, not only blocked the oridonin-induced increase in hydrogen peroxide and glutathione depletion, but also blocked apoptosis and senescence induced by oridonin, as evidenced by the decrease in Annexin V and senescence-associated β-galactosidase- positive cells and the inhibition of oridonin-induced upregulation of p53 and p16 and downregulation of c-Myc. Moreover, exogenous catalase could inhibit the increase in hydrogen peroxide and apoptosis induced by oridonin, but not the glutathione depletion and senescence. Furthermore, thioredoxin reductase (TrxR) activity was reduced by oridonin in vitro and in cells, which may cause the increase in hydrogen peroxide. In conclusion, the increase in hydrogen peroxide and glutathione depletion account for oridonin-induced apoptosis and senescence in colorectal cancer cells, and TrxR inhibition is involved in this process. Given the importance of TrxR as a novel cancer target in colon cancer, oridonin would be a promising clinical candidate. The mechanism of oridonin-induced inhibition of TrxR warrants further investigation.