Fengyun Zhao1, Yanni Huang2, Yingheng Zhang2, Xun Li3, Kaizhao Chen3, Yihao Long3, Fugui Li4, Xiaodong Ma5. 1. The Research Center of Basic Integrative Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, Guangdong, China. 20193101013@stu.gzucm.edu.cn. 2. The Research Center of Basic Integrative Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, Guangdong, China. 3. Institute for Brain Research and Rehabilitation, Guangdong Key Laboratory of Mental Health and Cognitive Science, Center for Studies of Psychological Application, South China Normal University, Guangzhou, 510631, Guangdong, China. 4. Cancer Research Institute of Zhongshan City, Zhongshan City People's Hospital, Zhongshan, 528403, Guangdong, China. 5. Institute for Brain Research and Rehabilitation, Guangdong Key Laboratory of Mental Health and Cognitive Science, Center for Studies of Psychological Application, South China Normal University, Guangzhou, 510631, Guangdong, China. sciencema@hotmail.com.
Abstract
PURPOSE: In this study, we sought to explore the function of seven important enzymes (MSMO1, EBP, HMGCS1, IDI2, DHCR7, FDFT1, and SQLE) involved in cholesterol biosynthesis especially SQLE in PDAC therapy. METHODS AND RESULTS: The TCGA and Oncomine dataset were used to explore the expression of the seven enzymes in normal and cancerous pancreatic individual, and their anti-proliferation efficiency against PDAC cells was measured by cell viability assay. Expression level and prognostic values of SQLE were evaluated by western blot and Kaplan-Meier analysis. The influence of SQLE knockdown by shRNA in PDAC cells was assessed by transwell, colony formation and cell cycle analysis. RNA-seq and GSEA were utilized to investigate the potential mechanisms. The synergistic effect of SQLE inhibitor, terbinafine, combined with six chemotherapeutic drugs in PDAC cells was tested by CCK-8 method. We demonstrated that downregulation of those enzymes especially SQLE significantly suppressed PDAC cells survival. SQLE was upregulated in PDAC cell lines, and the elevated level of SQLE was correlated with poor prognosis in pancreatic cancer samples. SQLE knockdown could significantly inhibit the proliferation and migration of PDAC cells. Cell cycle was blocked in S phase after SQLE silencing. Mechanistically, GSEA analysis with RNA-seq data revealed that SQLE silencing negatively mediated mTORC1 and TNFα/NF-κB signaling pathways. Besides, SQLE inhibitor terbinafine enhanced chemotherapeutic sensitivity of the six compounds. CONCLUSIONS: This study demonstrated that SQLE was a novel target for PDAC therapy. The synergism role of SQLE inhibition and chemotherapy may be potential therapeutic strategy for pancreatic cancer treatment.
PURPOSE: In this study, we sought to explore the function of seven important enzymes (MSMO1, EBP, HMGCS1, IDI2, DHCR7, FDFT1, and SQLE) involved in cholesterol biosynthesis especially SQLE in PDAC therapy. METHODS AND RESULTS: The TCGA and Oncomine dataset were used to explore the expression of the seven enzymes in normal and cancerous pancreatic individual, and their anti-proliferation efficiency against PDAC cells was measured by cell viability assay. Expression level and prognostic values of SQLE were evaluated by western blot and Kaplan-Meier analysis. The influence of SQLE knockdown by shRNA in PDAC cells was assessed by transwell, colony formation and cell cycle analysis. RNA-seq and GSEA were utilized to investigate the potential mechanisms. The synergistic effect of SQLE inhibitor, terbinafine, combined with six chemotherapeutic drugs in PDAC cells was tested by CCK-8 method. We demonstrated that downregulation of those enzymes especially SQLE significantly suppressed PDAC cells survival. SQLE was upregulated in PDAC cell lines, and the elevated level of SQLE was correlated with poor prognosis in pancreatic cancer samples. SQLE knockdown could significantly inhibit the proliferation and migration of PDAC cells. Cell cycle was blocked in S phase after SQLE silencing. Mechanistically, GSEA analysis with RNA-seq data revealed that SQLE silencing negatively mediated mTORC1 and TNFα/NF-κB signaling pathways. Besides, SQLE inhibitor terbinafine enhanced chemotherapeutic sensitivity of the six compounds. CONCLUSIONS: This study demonstrated that SQLE was a novel target for PDAC therapy. The synergism role of SQLE inhibition and chemotherapy may be potential therapeutic strategy for pancreatic cancer treatment.
Authors: M Castañeda-Ávila; A Cruz-Benítez; W Fuentes-Payán; A Maldonado-Albertorio; L Nieves-Ferrer; P Padró-Juarbe; R Soto-Abreu; N Pérez-Ríos; C R Torres-Cintrón; K J Ortiz-Ortiz; A P Ortiz Martinez Journal: Austin J Gastroenterol Date: 2016-04-08