Mathematical modelling unravels regulatory mechanisms of interferon--induced STAT1 serine-phosphorylation and MUC4 expression in pancreatic cancer cells

We recently reported that transforming growth factor-β (TGF-β) induces an increase in cytosolic Ca2+ ([Ca2+]cyt) in pancreatic cancer cells, but the mechanisms by which TGF-β mediates [Ca2+]cyt homeostasis in these cells are currently unknown. Transient receptor potential (TRP) channels and Na+/Ca2+ exchangers (NCX) are plasma membrane proteins that play prominent roles in controlling [Ca2+]cyt homeostasis in normal mammalian cells, but little is known regarding their roles in the regulation of [Ca2+]cyt in pancreatic cancer cells and pancreatic cancer development. Expression and function of NCX1 and TRPC1 proteins were characterized in BxPc3 pancreatic cancer cells. TGF-β induced both intracellular Ca2+ release and extracellular Ca2+ entry in these cells; however, 2-aminoethoxydiphenyl borate [2-APB; a blocker for both inositol 1,4,5-trisphosphate (IP3) receptor and TRPC], LaCl3 (a selective TRPC blocker), or KB-R7943 (a selective inhibitor for the Ca2+ entry mode of NCX) markedly inhibited the TGF-β-induced increase in [Ca2+]cyt. 2-APB or KB-R7943 treatment was able to dose-dependently reverse membrane translocation of PKCα induced by TGF-β. Transfection with small interfering RNA (siRNA) against NCX1 almost completely abolished NCX1 expression in BxPc3 cells and also inhibited PKCα serine phosphorylation induced by TGF-β. Knockdown of NCX1 or TRPC1 by specific siRNA transfection reversed TGF-β-induced pancreatic cancer cell motility. Therefore, TGF-β induces Ca2+ entry likely via TRPC1 and NCX1 and raises [Ca2+]cyt in pancreatic cancer cells, which is essential for PKCα activation and subsequent tumor cell invasion. Our data suggest that TRPC1 and NCX1 may be among the potential therapeutic targets for pancreatic cancer.

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Targeting interleukin-17 receptor B enhances gemcitabine sensitivity through downregulation of mucins in pancreatic cancer

Scientific Reports ◽

10.1038/s41598-020-73659-z ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Lung-Hung Tsai ◽

Kai-Wen Hsu ◽

Cheng-Ming Chiang ◽

Hsiu-Ju Yang ◽

Yu-Huei Liu ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Treatment ◽

Cancer Cells ◽

Neutralizing Antibody ◽

Interleukin 17 ◽

Targeting Therapy ◽

First Line Therapy ◽

Pancreatic Cancer Cells ◽

Muc4 Expression ◽

Pancreatic Cancer Therapy

Abstract Pancreatic cancer is the fourth leading cause of death worldwide due to its poorest prognoses with a 7% 5-year survival rate. Eighty percent of pancreatic cancer patients relapse after chemotherapy and develop early metastasis and drug resistance. Resistance to nucleoside analog gemcitabine frequently used in first-line therapy is an urgent issue in pancreatic cancer treatment. Expression of mucin (MUC) glycoproteins has been shown to enhance chemoresistance via increased cell stemness. Here we show interlukine-17 receptor B (IL-17RB) expression is positively correlated with MUC1 and MUC4 expression in pancreatic cancer cells and tumor tissue. Moreover, IL-17RB transcriptionally up-regulates expression of MUC1 and MUC4 to enhance cancer stem-like properties and resistance to gemcitabine. These results suggest IL-17RB can be a potential target for pancreatic cancer therapy. Indeed, treatment with IL-17RB-neutralizing antibody has a synergistic effect in combination with gemcitabine for killing pancreatic cancer cells. Altogether, these findings provide feasible applications for IL-17RB-targeting therapy in pancreatic cancer treatment.

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LncRNA SNHG16 induces the SREBP2 to promote lipogenesis and enhance the progression of pancreatic cancer

Future Oncology ◽

10.2217/fon-2019-0321 ◽

2019 ◽

Vol 15 (33) ◽

pp. 3831-3844 ◽

Cited By ~ 7

Author(s):

Yi Yu ◽

Jia-Tian Dong ◽

Bing He ◽

Yu-Feng Zou ◽

Xue-Song Li ◽

...

Keyword(s):

Pancreatic Cancer ◽

Wound Healing ◽

Cancer Cells ◽

Regulatory Mechanisms ◽

Luciferase Reporter ◽

Pancreatic Cancer Cells ◽

Diphenyltetrazolium Bromide ◽

Reporter Assays ◽

Oil Red O Staining ◽

Oil Red O

Aim: Blocking lipogenesis could significantly inhibit the progression of pancreatic cancer. Exploring the regulatory mechanisms of lipogenesis by lncRNA SNHG16 might be of great significance to control the development of pancreatic cancer. Methods: The proliferation, migration, invasion and lipogenesis were determined with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, wound healing, transwell and Oil Red O staining assays, respectively. The interactions among lncRNA SNHG16, miR-195 and SREBP2 were analyzed by dual luciferase reporter assays. Results: Both the knock down of lncRNA SNHG16 and SREBP2 and overexpression of miR-195 suppressed the proliferation, migration, invasion and lipogenesis in pancreatic cancer cells. LncRNA SNHG16 directly sponged miR-195 to modulate the lipogenesis via regulating the expression of SREBP2. Conclusion: LncRNA SNHG16 accelerated the development of pancreatic cancer and promoted lipogenesis via directly regulating miR-195/SREBP2 axis.

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