Diabetes Mellitus Stimulates Pancreatic Cancer Growth and Epithelial-mesenchymal Transition-mediated Metastasis Via a P38 MAPK Pathway

Overview

Journal Oncotarget

Specialty Oncology

Date 2016 Jul 15

PMID 27413117

Citations 22

Authors

Lishan Wang

Ying-Ying Bai

Yang Yang

Fangfang Hu

Yonghui Wang

Zeqian Yu

Zhangjun Cheng

Jiahua Zhou

Affiliations

Soon will be listed here.

Abstract

Diabetes mellitus (DM) and its accompanying chronic inflammation promote tumor progression. p38 mitogen-activated protein kinase (MAPK) is an essential kinase for inflammation. The effects of p38 MAPK on epithelial-mesenchymal transition (EMT)-mediated diabetic pancreatic cancer metastasis remain unclear. Here, we demonstrate that p38 MAPK phosphorylation was significantly increased in pancreatic cancer cells treated with high glucose and in pancreatic tumors from diabetic animals. A p38 MAPK inhibitor significantly suppressed the proliferation and invasion of pancreatic cancer cells under high-glucose conditions. Moreover, p38 MAPK inhibition not only significantly decreased both the tumor volume monitored by magnetic resonance imaging and EMT-related metastasis but also increased the survival of diabetic mice bearing pancreatic tumors. Furthermore, the inflammation in diabetic animals bearing pancreatic tumors was also significantly lower after therapy. Collectively, our findings reveal that p38 MAPK inhibitors may provide a novel intervention strategy for diabetic pancreatic cancer treatment.

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References

Ryu T, Park J, Scherer P . Hyperglycemia as a risk factor for cancer progression. Diabetes Metab J. 2014; 38(5):330-6. PMC: 4209346. DOI: 10.4093/dmj.2014.38.5.330. View

Aggarwal B, Sethi G, Ahn K, Sandur S, Pandey M, Kunnumakkara A . Targeting signal-transducer-and-activator-of-transcription-3 for prevention and therapy of cancer: modern target but ancient solution. Ann N Y Acad Sci. 2007; 1091:151-69. DOI: 10.1196/annals.1378.063. View

Liu H, Ma Q, Li J . High glucose promotes cell proliferation and enhances GDNF and RET expression in pancreatic cancer cells. Mol Cell Biochem. 2010; 347(1-2):95-101. DOI: 10.1007/s11010-010-0617-0. View

Guerra C, Schuhmacher A, Canamero M, Grippo P, Verdaguer L, Perez-Gallego L . Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. Cancer Cell. 2007; 11(3):291-302. DOI: 10.1016/j.ccr.2007.01.012. View

Karin M . Nuclear factor-kappaB in cancer development and progression. Nature. 2006; 441(7092):431-6. DOI: 10.1038/nature04870. View

Lv Z, Wang Q, Wan Q, Lin J, Hu M, Liu Y . The role of the p38 MAPK signaling pathway in high glucose-induced epithelial-mesenchymal transition of cultured human renal tubular epithelial cells. PLoS One. 2011; 6(7):e22806. PMC: 3146517. DOI: 10.1371/journal.pone.0022806. View

Ono K, Han J . The p38 signal transduction pathway: activation and function. Cell Signal. 2000; 12(1):1-13. DOI: 10.1016/s0898-6568(99)00071-6. View

Yasui H, Hideshima T, Ikeda H, Jin J, Ocio E, Kiziltepe T . BIRB 796 enhances cytotoxicity triggered by bortezomib, heat shock protein (Hsp) 90 inhibitor, and dexamethasone via inhibition of p38 mitogen-activated protein kinase/Hsp27 pathway in multiple myeloma cell lines and inhibits paracrine tumour growth. Br J Haematol. 2006; 136(3):414-23. DOI: 10.1111/j.1365-2141.2006.06443.x. View

Li D . Diabetes and pancreatic cancer. Mol Carcinog. 2011; 51(1):64-74. PMC: 3238796. DOI: 10.1002/mc.20771. View

10.

Li W, Ma Z, Ma J, Li X, Xu Q, Duan W . Hydrogen peroxide mediates hyperglycemia-induced invasive activity via ERK and p38 MAPK in human pancreatic cancer. Oncotarget. 2015; 6(31):31119-33. PMC: 4741592. DOI: 10.18632/oncotarget.5045. View

11.

Gupta S, Kim J, Kannappan R, Reuter S, Dougherty P, Aggarwal B . Role of nuclear factor κB-mediated inflammatory pathways in cancer-related symptoms and their regulation by nutritional agents. Exp Biol Med (Maywood). 2011; 236(6):658-71. PMC: 3141285. DOI: 10.1258/ebm.2011.011028. View

12.

Jiang G, Xie W, Wang H, Du J, Wu B, Xu W . Curcumin combined with FAPαc vaccine elicits effective antitumor response by targeting indolamine-2,3-dioxygenase and inhibiting EMT induced by TNF-α in melanoma. Oncotarget. 2015; 6(28):25932-42. PMC: 4694876. DOI: 10.18632/oncotarget.4577. View

13.

Leelahavanichkul K, Amornphimoltham P, Molinolo A, Basile J, Koontongkaew S, Gutkind J . A role for p38 MAPK in head and neck cancer cell growth and tumor-induced angiogenesis and lymphangiogenesis. Mol Oncol. 2013; 8(1):105-18. PMC: 3946852. DOI: 10.1016/j.molonc.2013.10.003. View

14.

Zhou J, Yu Z, Zhao S, Hu L, Zheng J, Yang D . Lentivirus-based DsRed-2-transfected pancreatic cancer cells for deep in vivo imaging of metastatic disease. J Surg Res. 2009; 157(1):63-70. DOI: 10.1016/j.jss.2008.08.027. View

15.

Iwatsuki M, Mimori K, Yokobori T, Ishi H, Beppu T, Nakamori S . Epithelial-mesenchymal transition in cancer development and its clinical significance. Cancer Sci. 2009; 101(2):293-9. PMC: 11159985. DOI: 10.1111/j.1349-7006.2009.01419.x. View

16.

Guan J, Zhang H, Wen Z, Gu Y, Cheng Y, Sun Y . Retinoic acid inhibits pancreatic cancer cell migration and EMT through the downregulation of IL-6 in cancer associated fibroblast cells. Cancer Lett. 2013; 345(1):132-9. DOI: 10.1016/j.canlet.2013.12.006. View

17.

Partecke I, Kaeding A, Sendler M, Albers N, Kuhn J, Speerforck S . In vivo imaging of pancreatic tumours and liver metastases using 7 Tesla MRI in a murine orthotopic pancreatic cancer model and a liver metastases model. BMC Cancer. 2011; 11:40. PMC: 3039629. DOI: 10.1186/1471-2407-11-40. View

18.

Gupta J, Del Barco Barrantes I, Igea A, Sakellariou S, Pateras I, Gorgoulis V . Dual function of p38α MAPK in colon cancer: suppression of colitis-associated tumor initiation but requirement for cancer cell survival. Cancer Cell. 2014; 25(4):484-500. DOI: 10.1016/j.ccr.2014.02.019. View

19.

Lim S, Lee Y, Lee E . p38MAPK inhibitor SB203580 sensitizes human SNU-C4 colon cancer cells to exisulind-induced apoptosis. Oncol Rep. 2006; 16(5):1131-5. View

20.

Soreide K, Sund M . Epidemiological-molecular evidence of metabolic reprogramming on proliferation, autophagy and cell signaling in pancreas cancer. Cancer Lett. 2014; 356(2 Pt A):281-8. DOI: 10.1016/j.canlet.2014.03.028. View