Inhibition of cell growth and induction of apoptosis in non-small cell lung cancer cells by delta-tocotrienol is associated with notch-1 down-regulation

Abstract

Lung cancer is the leading cause of death among all cancers. Non-small cell lung cancer accounts for 80% of lung cancer with a 5-year survival rate of 16%. Notch pathway, especially Notch-1 is up-regulated in a subgroup of non-small cell lung cancer patients. Since Notch-1 signaling plays an important role in cell proliferation, differentiation, and apoptosis, down-regulation of Notch-1 may exert anti-tumor effects. The objective of this study was to investigate whether delta-tocotrienol, a naturally occurring isoform of Vitamin E, inhibits non-small cell lung cancer cell growth via Notch signaling. Treatment with delta-tocotrienol resulted in a dose and time dependent inhibition of cell growth, cell migration, tumor cell invasiveness, and induction of apoptosis. Real-time RT-PCR and western blot analysis showed that antitumor activity by delta-tocotrienol was associated with a decrease in Notch-1, Hes-1, Survivin, MMP-9, VEGF, and Bcl-XL expression. In addition, there was a decrease in NF-κB-DNA binding activity. These results suggest that down-regulation of Notch-1, via inhibition of NF-κB signaling pathways by delta-tocotrienol, could provide a potential novel approach for prevention of tumor progression in non-small cell lung cancer.

Tocotrienol-rich mixture inhibits cell proliferation and induces apoptosis via down-regulation of the Notch-1/NF-κB pathways in NSCLC cells

“…Further insight into the molecular mechanism of Notch-1 pathway and its target genes, Notch-1/Hes-1 pathways have been reported to be upstream to NF-κB activation in lung cancer and leukemia cells. 10,42 According to the current evidence, Notch ligands induced NF-κB activation in leukemia cells and decreased Notch-1 lowered NF-κB DNA-binding activity. 43 Another study also reported that mice with reduced Notch activities had a significantly decreased NF-κB activity.…”

“…10,11 Although the role of different Notch transmembrane receptors in NSCLC development is not completely understood, Notch-1 is considered to play a vital role in cancer development [12][13][14][15] compared with other Notch transmembrane receptors. For instance, Notch-1 shows a growth-promoting function on NSCLC, whereas in SCLC, it plays a tumor-suppressive role.…”

“…Our previous study clearly showed that delta-tocotrienol inhibits NF-κB signaling pathways via downregulation of Notch-1, thereby inhibiting the proliferation, metastatic/invasive potential while inducing apoptosis of NSCLC adenocarcinoma cells in a dose-dependent manner. 10,[24][25][26] However, overall effects of tocotrienols on NSCLC are still not well understood.…”

Cigarette smoke induces the expression of Notch3, not Notch1, protein in lung adenocarcinoma

“…The activation of the Notch1 signaling pathway also has downstream effects on protein kinase casein kinase 2α (34), Ras (35) and tribbles homolog 3 (36). The activation of Notch1 may contribute to drug resistance in LAC, since the downregulation of Notch1 has been found to be effective during treatment with δ-tocotrienol (37)(38)(39), gefitinib (40,41), cisplatin (42) or pterostilbene (43). Blocking Notch1 has been identified to inhibit the growth of cluster of differentiation 133-positive cancer cells (44).…”

Blocking NOTCH pathway can enhance the effect of EGFR inhibitor through targeting CD133+ endometrial cancer cells

“…18,19 However, some research has demonstrated contradictory results, which suggested that the Notch pathway has tumor-suppressive function rather than oncogenic role in human EC cells . 20 As an example, the downregulation of Notch signaling inhibits the growth, migration, and invasiveness of cancer cells and induces cell apoptosis . 21 In the current study, we found that Notch signaling was expressed in both CD133C and CD133-cells.…”