MicroRNA-21-mediated regulation of Sprouty2 protein expression enhances the cytotoxic effect of 5-fluorouracil and metformin in colon cancer cells.

Sprouty2 (Spry2) was identified recently as a tumor suppressor gene in cancer cells which inhibits the activation of receptor tyrosine kinases (RTKs). The present study explored the effect of Spry2 in colon cancer cells in order to assess its potential use in the treatment of colon cancer. Expression of Spry2 inhibited the growth of a colon cancer cell line, HCT116, and induced sensitization to fluorouracil (5-FU) and metformin. Spry2 promoted apoptosis of cancer cells in association with activation of the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) pathway and the blockade of Ras-Raf-Erk signaling. Treatment of Spry2-HCT116 cells with metformin resulted in a more prominent effect on the inhibition of cell migration. Inhibition of microRNA-21 (mir‑21) induced upregulation of Spry2 and PTEN which underscores the importance of mir-21 in Spry2-associated tumorigenesis of the colon. These results point toward a potential strategy for colon cancer treatment worthy of further investigation.

[1]  Matthew Freeman,et al.  Sprouty, an Intracellular Inhibitor of Ras Signaling , 1999, Cell.

[2]  J. Massagué,et al.  Cloning of p57KIP2, a cyclin-dependent kinase inhibitor with unique domain structure and tissue distribution. , 1995, Genes & development.

[3]  E. Nishida,et al.  Sprouty1 and Sprouty2 provide a control mechanism for the Ras/MAPK signalling pathway , 2002, Nature Cell Biology.

[4]  S. Baker,et al.  The Tumor Suppressor PTEN Is Necessary for Human Sprouty 2-mediated Inhibition of Cell Proliferation* , 2006, Journal of Biological Chemistry.

[5]  G. Woude,et al.  Overexpression of sprouty 2 inhibits HGF/SF-mediated cell growth, invasion, migration, and cytokinesis , 2004, Oncogene.

[6]  Jonathan D. Licht,et al.  Mammalian Sprouty Proteins Inhibit Cell Growth and Differentiation by Preventing Ras Activation* , 2001, The Journal of Biological Chemistry.

[7]  O. Warburg.  On the origin of cancer cells. , 1956, Science.

[8]  George A Calin,et al.  MicroRNA expression profiles associated with prognosis and therapeutic outcome in colon adenocarcinoma. , 2008, JAMA.

[9]  Jan-Gowth Chang,et al.  Deregulated expression of sprouty2 and microRNA-21 in human colon cancer: Correlation with the clinical stage of the disease , 2011, Cancer biology & therapy.

[10]  D. Bar-Sagi,et al.  The bimodal regulation of epidermal growth factor signaling by human Sprouty proteins , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[11]  N. Hacohen,et al.  sprouty Encodes a Novel Antagonist of FGF Signaling that Patterns Apical Branching of the Drosophila Airways , 1998, Cell.

[12]  D. Bar-Sagi,et al.  Modulation of signalling by Sprouty: a developing story , 2004, Nature Reviews Molecular Cell Biology.

[13]  H. Nielsen,et al.  High levels of microRNA-21 in the stroma of colorectal cancers predict short disease-free survival in stage II colon cancer patients , 2010, Clinical & Experimental Metastasis.

[14]  B. Viollet,et al.  Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. , 2007, Cancer research.

[15]  V. Litvak,et al.  Sprouty Fine-Tunes EGF Signaling through Interlinked Positive and Negative Feedback Loops , 2003, Current Biology.

[16]  G. Guy,et al.  Sprouty proteins are targeted to membrane ruffles upon growth factor receptor tyrosine kinase activation: Identification of a novel translocation domain , 2000 .

[17]  W. Schulz,et al.  Concomitant down-regulation of SPRY1 and SPRY2 in prostate carcinoma. , 2006, Endocrine-related cancer.

[18]  N. Miller,et al.  MicroRNA-21 and PDCD4 expression in colorectal cancer. , 2011, European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology.

[19]  B. Shilo,et al.  Sprouty is a general inhibitor of receptor tyrosine kinase signaling. , 1999, Development.

[20]  R. Shaw,et al.  Glucose metabolism and cancer. , 2006, Current opinion in cell biology.

[21]  T. Putti,et al.  The Ras/Mitogen-Activated Protein Kinase Pathway Inhibitor and Likely Tumor Suppressor Proteins, Sprouty 1 and Sprouty 2 Are Deregulated in Breast Cancer , 2004, Cancer Research.

[22]  Lewis C Cantley,et al.  The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[23]  M. Shibuya,et al.  Mammalian Sprouty4 suppresses Ras-independent ERK activation by binding to Raf1 , 2003, Nature Cell Biology.

[24]  Wan-Wan Lin,et al.  5-Aminoimidazole-4-carboxamide riboside sensitizes TRAIL- and TNFα-induced cytotoxicity in colon cancer cells through AMP-activated protein kinase signaling , 2007, Molecular Cancer Therapeutics.

[25]  Kei Sakamoto,et al.  LKB1-dependent signaling pathways. , 2006, Annual review of biochemistry.

[26]  M. Birnbaum,et al.  AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus , 2004, Nature.

[27]  S. So,et al.  Sprouty 2, an inhibitor of mitogen-activated protein kinase signaling, is down-regulated in hepatocellular carcinoma. , 2006, Cancer research.

[28]  D. Bar-Sagi,et al.  hSpry2 Is Targeted to the Ubiquitin-Dependent Proteasome Pathway by c-Cbl , 2003, Current Biology.

[29]  G. Guy,et al.  The Cysteine-Rich Sprouty Translocation Domain Targets Mitogen-Activated Protein Kinase Inhibitory Proteins to Phosphatidylinositol 4,5-Bisphosphate in Plasma Membranes , 2002, Molecular and Cellular Biology.

[30]  N. Hacohen,et al.  Sprouty: a common antagonist of FGF and EGF signaling pathways in Drosophila. , 1999, Development.

[31]  N. Sonenberg,et al.  Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells. , 2007, Cancer research.

[32]  Nahum Sonenberg,et al.  Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. , 2006, Cancer research.