Akt signaling is sustained by a CD44 splice isoform–mediated positive feedback loop

Cancer Research

Volumn 77, Issue 14, 2017, Pages 3791-3801

  Liu, Sali ^a,b   Cheng, Chonghui ^a,b  

^a BAYLOR COLLEGE OF MEDICINE   (United States)

^b NORTHWESTERN UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1,4 DIAMINO 1,4 BIS(2 AMINOPHENYLTHIO) 2,3 DICYANOBUTADIENE; 2 MORPHOLINO 8 PHENYLCHROMONE; 2,3 DIHYDRO 2 OXO 3 (4,5,6,7 TETRAHYDRO 1H INDOL 2 YLMETHYLENE) 1H INDOLE 5 SULFONIC ACID DIMETHYLAMIDE; 8 [4 (1 AMINOCYCLOBUTYL)PHENYL] 9 PHENYL 1,2,4 TRIAZOLO[3,4 F][1,6]NAPHTHYRIDIN 3(2H) ONE; CD44V ANTIGEN; CISPLATIN; HYALURONAN SYNTHASE HAS2; MESSENGER RNA; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN KINASE B; SYNTHETASE; TRANSCRIPTION FACTOR FKHR; UNCLASSIFIED DRUG; CD44 PROTEIN, HUMAN; FOXO1 PROTEIN, HUMAN; GLUCURONOSYLTRANSFERASE; HAS2 PROTEIN, HUMAN; HERMES ANTIGEN; ISOPROTEIN;

ANTIGEN EXPRESSION; ANTINEOPLASTIC ACTIVITY; ARTICLE; AUTOREGULATION; BREAST CANCER; BREAST CARCINOGENESIS; CANCER CELL; CANCER SURVIVAL; CONTROLLED STUDY; ENZYME ACTIVATION; ENZYME INHIBITION; EPITHELIAL MESENCHYMAL TRANSITION; FEEDBACK SYSTEM; GENETIC TRANSCRIPTION; HAS2 GENE; HUMAN; HUMAN CELL; PHENOTYPE; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN PHOSPHORYLATION; SIGNAL TRANSDUCTION; TRANSCRIPTION REGULATION; BREAST TUMOR; CELL SURVIVAL; ENZYMOLOGY; FEMALE; GENETICS; HEK293 CELL LINE; METABOLISM; PHYSIOLOGICAL FEEDBACK; PHYSIOLOGY; TUMOR CELL LINE;

ANTIGENS, CD44; BREAST NEOPLASMS; CELL LINE, TUMOR; CELL SURVIVAL; FEEDBACK, PHYSIOLOGICAL; FEMALE; FORKHEAD BOX PROTEIN O1; GLUCURONOSYLTRANSFERASE; HEK293 CELLS; HUMANS; PROTEIN ISOFORMS; PROTO-ONCOGENE PROTEINS C-AKT; SIGNAL TRANSDUCTION;

EID: 85023756242     PISSN: 00085472     EISSN: 15387445     Source Type: Journal    
DOI: 10.1158/0008-5472.CAN-16-2545     Document Type: Article

References (55)

1. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144:646–74.
2. Sordella R, Bell DW, Haber DA, Settleman J. Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science 2004;305:1163–7.
3. Adams JM, Cory S. The Bcl-2 protein family: arbiters of cell survival. Science 1998;281:1322–6.
4. Meredith JE Jr, Fazeli B, Schwartz MA. The extracellular matrix as a cell survival factor. Mol Biol Cell 1993;4:953–61.
5. Carracedo A, Ma L, Teruya-Feldstein J, Rojo F, Salmena L, Alimonti A, et al. Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest 2008; 118:3065–74.
6. Li H, Yang B, Huang J, Lin Y, Xiang T, Wan J, et al. Cyclo-oxygenase-2 in tumor-associated macrophages promotes breast cancer cell survival by triggering a positive-feedback loop between macrophages and cancer cells. Oncotarget 2015;6: 29637–50.
7. Su S, Liu Q, Chen J, Chen J, Chen F, He C, et al. A positive feedback loop between mesenchymal-like cancer cells and macrophages is essential to breast cancer metastasis. Cancer Cell 2014; 25:605–20.
8. O'Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D, et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 2006;66:1500–8.
9. Hennessy BT, Smith DL, Ram PT, Lu Y, Mills GB. Exploiting the PI3K/ AKT pathway for cancer drug discovery. Nat Rev Drug Discov 2005; 4:988–1004.
10. Kang S, Bader AG, Vogt PK. Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic. Proc Natl Acad Sci U S A 2005;102:802–7.
11. Page C, Lin HJ, Jin Y, Castle VP, Nunez G, Huang M, et al. Overexpression of Akt/AKT can modulate chemotherapy-induced apoptosis. Anticancer Res 2000;20:407–16.
12. Cheng JQ, Godwin AK, Bellacosa A, Taguchi T, Franke TF, Hamilton TC, et al. AKT2, a putative oncogene encoding a member of a subfamily of protein-serine/threonine kinases, is amplified in human ovarian carcinomas. Proc Natl Acad Sci U S A 1992;89:9267–71.
13. Sun M, Wang G, Paciga JE, Feldman RI, Yuan ZQ, Ma XL, et al. AKT1/ PKBalpha kinase is frequently elevated in human cancers and its constitutive activation is required for oncogenic transformation in NIH3T3 cells. Am J Pathol 2001;159:431–7.
14. Graveley BR. Alternative splicing: increasing diversity in the proteomic world. Trends Genet 2001;17:100–7.
15. Nilsen TW, Graveley BR. Expansion of the eukaryotic proteome by alternative splicing. Nature 2010;463:457–63.
16. Liu S, Cheng C. Alternative RNA splicing and cancer. Wiley Interdiscip Rev RNA 2013;4:547–66.
17. David CJ, Manley JL. Alternative pre-mRNA splicing regulation in cancer: pathways and programs unhinged. Genes Dev 2010;24:2343–64.
18. Cheng C, Yaffe MB, Sharp PA. A positive feedback loop couples Ras activation and CD44 alternative splicing. Genes Dev 2006;20:1715–20.
19. Zhao P, Damerow MS, Stern P, Liu AH, Sweet-Cordero A, Siziopikou K, et al. CD44 promotes Kras-dependent lung adenocarcinoma. Oncogene 2013;32:5186–90.
20. Matter N, Herrlich P, Konig H. Signal-dependent regulation of splicing via phosphorylation of Sam68. Nature 2002;420:691–5.
21. Brown RL, Reinke LM, Damerow MS, Perez D, Chodosh LA, Yang J, et al. CD44 splice isoform switching in human and mouse epithelium is essential for epithelial-mesenchymal transition and breast cancer progression. J Clin Invest 2011;121:1064–74.
22. Okabe H, Ishimoto T, Mima K, Nakagawa S, Hayashi H, Kuroki H, et al. CD44s signals the acquisition of the mesenchymal phenotype required for anchorage-independent cell survival in hepatocellular carcinoma. Br J Cancer 2014;110:958–66.
23. Reinke LM, Xu Y, Cheng C. Snail represses the splicing regulator epithelial splicing regulatory protein 1 to promote epithelial-mesenchymal transition. J Biol Chem 2012;287:36435–42.
24. Xu Y, Gao XD, Lee JH, Huang H, Tan H, Ahn J, et al. Cell type-restricted activity of hnRNPM promotes breast cancer metastasis via regulating alternative splicing. Genes Dev 2014;28:1191–203.
25. Zheng X, Carstens JL, Kim J, Scheible M, Kaye J, Sugimoto H, et al. Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature 2015;527: 525–30.
26. Fischer KR, Durrans A, Lee S, Sheng J, Li F, Wong ST, et al. Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature 2015;527:472–6.
27. Monslow J, Williams JD, Guy CA, Price IK, Craig KJ, Williams HJ, et al. Identification and analysis of the promoter region of the human hyaluronan synthase 2 gene. J Biol Chem 2004;279:20576–81.
28. Torre C, Wang SJ, Xia W, Bourguignon LY. Reduction of hyaluronan-CD44-mediated growth, migration, and cisplatin resistance in head and neck cancer due to inhibition of Rho kinase and PI-3 kinase signaling. Arch Otolaryngol Head Neck Surg 2010;136:493–501.
29. Kim MS, Park MJ, Moon EJ, Kim SJ, Lee CH, Yoo H, et al. Hyaluronic acid induces osteopontin via the phosphatidylinositol 3-kinase/Akt pathway to enhance the motility of human glioma cells. Cancer Res 2005;65:686–91.
30. Tian X, Azpurua J, Hine C, Vaidya A, Myakishev-Rempel M, Ablaeva J, et al. High-molecular-mass hyaluronan mediates the cancer resistance of the naked mole rat. Nature 2013;499:346–9.
31. Nandi A, Estess P, Siegelman MH. Hyaluronan anchoring and regulation on the surface of vascular endothelial cells is mediated through the functionally active form of CD44. J Biol Chem 2000; 275:14939–48.
32. Girbl T, Hinterseer E, Grossinger EM, Asslaber D, Oberascher K, Weiss L, et al. CD40-mediated activation of chronic lymphocytic leukemia cells promotes their CD44-dependent adhesion to hyaluronan and restricts CCL21-induced motility. Cancer Res 2013;73:561–70.
33. Aguirre-Alvarado C, Segura-Cabrera A, Velazquez-Quesada I, Hernandez-Esquivel MA, Garcia-Perez CA, Guerrero-Rodriguez SL, et al. Virtual screening-driven repositioning of etoposide as CD44 antagonist in breast cancer cells. Oncotarget 2016;7:23772–84.
34. Calnan DR, Brunet A. The FoxO code. Oncogene 2008;27:2276–88.
35. Paoli P, Giannoni E, Chiarugi P. Anoikis molecular pathways and its role in cancer progression. Biochim Biophys Acta 2013;1833:3481–98.
36. Larue L, Bellacosa A. Epithelial-mesenchymal transition in development and cancer: role of phosphatidylinositol 30 kinase/AKT pathways. Oncogene 2005;24:7443–54.
37. Bernert B, Porsch H, Heldin P. Hyaluronan synthase 2 (HAS2) promotes breast cancer cell invasion by suppression of tissue metalloproteinase inhibitor 1 (TIMP-1). J Biol Chem 2011;286:42349–59.
38. Urakawa H, Nishida Y, Wasa J, Arai E, Zhuo L, Kimata K, et al. Inhibition of hyaluronan synthesis in breast cancer cells by 4-methylumbelliferone suppresses tumorigenicity in vitro and metastatic lesions of bone in vivo. Int J Cancer 2012;130:454–66.
39. Li Y, Li L, Brown TJ, Heldin P. Silencing of hyaluronan synthase 2 suppresses the malignant phenotype of invasive breast cancer cells. Int J Cancer 2007;120:2557–67.
40. Chanmee T, Ontong P, Mochizuki N, Kongtawelert P, Konno K, Itano N. Excessive hyaluronan production promotes acquisition of cancer stem cell signatures through the coordinated regulation of Twist and the transforming growth factor beta (TGF-beta)-Snail signaling axis. J Biol Chem 2014;289:26038–56.
41. Okuda H, Kobayashi A, Xia B, Watabe M, Pai SK, Hirota S, et al. Hyaluronan synthase HAS2 promotes tumor progression in bone by stimulating the interaction of breast cancer stem-like cells with macrophages and stromal cells. Cancer Res 2012;72:537–47.
42. Udabage L, Brownlee GR, Waltham M, Blick T, Walker EC, Heldin P, et al. Antisense-mediated suppression of hyaluronan synthase 2 inhibits the tumorigenesis and progression of breast cancer. Cancer Res 2005; 65:6139–50.
43. Makkonen KM, Pasonen-Seppanen S, Torronen K, Tammi MI, Carlberg C. Regulation of the hyaluronan synthase 2 gene by convergence in cyclic AMP response element-binding protein and retinoid acid receptor signaling. J Biol Chem 2009;284:18270–81.
44. Schiller M, Dennler S, Anderegg U, Kokot A, Simon JC, Luger TA, et al. Increased cAMP levels modulate transforming growth factor-beta/Smad-induced expression of extracellular matrix components and other key fibroblast effector functions. J Biol Chem 2010;285:409–21.
45. Okegawa T, Ushio K, Imai M, Morimoto M, Hara T. Orphan nuclear receptor HNF4G promotes bladder cancer growth and invasion through the regulation of the hyaluronan synthase 2 gene. Oncogenesis 2013;2: e58.
46. Yu Q, Stamenkovic I. Localization of matrix metalloproteinase 9 to the cell surface provides a mechanism for CD44-mediated tumor invasion. Genes Dev 1999;13:35–48.
47. Ouhtit A, Abd Elmageed ZY, Abdraboh ME, Lioe TF, Raj MH. In vivo evidence for the role of CD44s in promoting breast cancer metastasis to the liver. Am J Pathol 2007;171:2033–9.
48. Godar S, Ince TA, Bell GW, Feldser D, Donaher JL, Bergh J, et al. Growth-inhibitory and tumor-suppressive functions of p53 depend on its repression of CD44 expression. Cell 2008;134:62–73.
49. Zhao P, Xu Y, Wei Y, Qiu Q, Chew TL, Kang Y, et al. The CD44s splice isoform is a central mediator for invadopodia activity. J Cell Sci 2016;129:1355–65.
50. Lopez JI, Camenisch TD, Stevens MV, Sands BJ, McDonald J, Schroeder JA. CD44 attenuates metastatic invasion during breast cancer progression. Cancer Res 2005;65:6755–63.
51. Gao AC, Lou W, Dong JT, Isaacs JT. CD44 is a metastasis suppressor gene for prostatic cancer located on human chromosome 11p13. Cancer Res 1997;57:846–9.
52. Cheng C, Sharp PA. Regulation of CD44 alternative splicing by SRm160 anditspotentialroleintumorcellinvasion. Mol Cell Biol 2006;26:362–70.
53. Ponta H, Sherman L, Herrlich PA. CD44: from adhesion molecules to signalling regulators. Nat Rev Mol Cell Biol 2003;4:33–45.
54. Goehe RW, Shultz JC, Murudkar C, Usanovic S, Lamour NF, Massey DH, et al. hnRNP L regulates the tumorigenic capacity of lung cancer xenografts in mice via caspase-9 pre-mRNA processing. J Clin Invest 2010;120:3923–39.
55. Nitulescu GM, Margina D, Juzenas P, Peng Q, Olaru OT, Saloustros E, et al. Akt inhibitors in cancer treatment: the long journey from drug discovery to clinical use (Review). Int J Oncol 2016;48:869–85.