Background: Pancreatic cancer, a lethal and aggressive malignancy is the fourth leading cause of cancer-related deaths in the United States. One of the main reasons for this outcome includes the lack of effective prevention strategies for recurrent disease. Pancreatic cancer stem cells (CSCs) have been implicated in the development of pancreatic cancer metastasis, resistance to chemotherapy and its recurrence following surgical extirpation. We have shown that natural vitamin E δ-tocotrienol is the most bioactive tocotrienols against pancreatic cancer in vitro as well as in vivo models. The purpose of this study was to evaluate the effect of δ-tocotrienol on tumor metastatic EMT, migration, invasion, angiogenesis and CSCs signaling in metastatic human pancreatic cancer cells.
Methods: Human metastatic pancreatic cancer cells L3.6pl expressing luciferase were orthotopically implanted into pancreas of Athymic nude mice (n = 10) and after one week they were randomized in two groups: 1) vehicle control (ethanol extracted olive oil) and 2) δ-tocotrienol (200 mg/kg, orally twice a day) for 4 weeks. The tumor volume, tumor weight, liver and lung metastasis were recorded. The tumor tissues were analyzed for metastasis markers, epithelial to mesenchymal transition (EMT), and angiogenesis. In vitro L3.6pl cells were treated with δ-tocotrienol (50 μM) and used for migration and invasion assay, isolation of CSCs and spheroid formation, transcription factors and CSCs signaling markers were determined by Western blotting.
Results: Vitamin E δ-tocotrienol significantly inhibited the pancreatic tumor growth [tumor volume (50%) and weight (60%)] and metastasis in the liver and lung, CSCs spheroid formation, migration and invasion compared to control. δ-tocotrienol induced apoptosis (PARP1 cleavage and Bax expression) compared to control. δ-tocotrienol also inhibited EMT (E-cadherin to vimentin), metastasis (MMP9), angiogenesis (VEGF), CSCs transcription factors (Nanog, Oct4, Sox2 and KLF4) and oncogenic signaling (Notch-1 and pERK) compared to control.
Conclusion: Vitamin E δ-tocotrienol inhibited metastasis of human pancreatic tumor through inhibition of EMT, migration, invasion, angiogenesis, cancer stem cell signaling and induction of apoptosis.
Citation Format: Kazim Husain, Said M. Sebti, Mokenge P. Malafa. Vitamin E delta-tocotrienol inhibits metastasis and targets cancer stem cell signaling in human pancreatic cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4383. doi:10.1158/1538-7445.AM2015-4383