Significance of Caveolin-1 Regulators in Pancreatic Cancer

  • Chen, Tao (Department of Pancreas and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center) ;
  • Liu, Liang (Department of Pancreas and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center) ;
  • Xu, Hua-Xiang (Department of Pancreas and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center) ;
  • Wang, Wen-Quan (Department of Pancreas and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center) ;
  • Wu, Chun-Tao (Department of Pancreas and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center) ;
  • Yao, Wan-Tong (Department of Pancreas and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center) ;
  • Yu, Xian-Jun (Department of Pancreas and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center)
  • Published : 2013.08.30


Caveolin-1 is a scaffold protein on the cell membrane. As the main component of caveolae, caveolin-1 is involved in many biological processes that include substance uptake and transmembrane signaling. Many of these processes and thus caveolin-1 contribute to cell transformation, tumorigenesis, and metastasis. Of particular interest are the dual rolesof tumor suppressor and oncogene that caveolin-1 appear to play in different malignancies, including pancreatic cancer. Therefore, analyzing caveolin-1 regulators and understanding their mechanisms of actionis key to identifying novel diagnostic and therapeutic tools for pancreatic cancer. This review details the mechanisms of action of caveolin-1 regulators and the potential significance for pancreatic cancer treatment.


Caveolae;caveolin-1;pancreatic cancer;regulatory factor;significance


  1. Mochizuki T, Furuta S, Mitsushita J, et al (2006). Inhibition of NADPH oxidase 4 activates apoptosis via the AKT/apoptosis signal-regulating kinase 1 pathway in pancreatic cancer PANC-1 cells. Oncogene, 25, 3699-707.
  2. Murakami S, Miyamoto M, Hida Y, et al (2003). Caveolin-I overexpression is a favourable prognostic factor for patients with extrahepatic bile duct carcinoma. Br J Cancer, 88, 1234-8.
  3. Nam S, Wen W, Schroeder A, et al (2012). Dual inhibition of Janus and Src family kinases by novel indirubin derivative blocks constitutively-activated Stat3 signaling associated with apoptosis of human pancreatic cancer cells. Mol Oncol, 7, 369-78.
  4. Nimri L, Barak H, Graeve L, et al (2012). Restoration of caveolin-1 expression suppresses growth, membrane-type-4 metalloproteinase expression and metastasis-associated activities in colon cancer cells. Mol Carcinog. doi: 10.1002/mc.21927.
  5. Okamoto T, Schlegel A, Scherer PE, et al (1998). Caveolins, a family of scaffolding proteins for organizing “preassembled signaling complexes” at the plasma membrane. J Biol Chem, 273, 5419-22.
  6. Parat MO, Fox PL (2004). Oxidative stress, caveolae and caveolin-1. Subcell Biochem, 37, 425-41.
  7. Parat MO, Stachowicz RZ, Fox PL (2002). Oxidative stress inhibits caveolin-1 palmitoylation and trafficking in endothelial cells. Biochem J, 361, 681-8.
  8. Prinetti A, Aureli M, Illuzzi G, et al (2010). GM3 synthase overexpression results in reduced cell motility and in caveolin-1 upregulation in human ovarian carcinoma cells. Glycobiology, 20, 62-77.
  9. Rao X, Evans J, Chae H, et al (2012). CpG island shore methylation regulates caveolin-1 expression in breast cancer. Oncogene. doi: 10.1038/onc.2012.474.
  10. Razani B, Woodman SE, Lisanti MP (2002). Caveolae: from cell biology to animal physiology. Pharmacol Rev, 54, 431-67.
  11. Roy SK, Srivastava RK, Shankar S (2010). Inhibition of PI3K/AKT and MAPK/ERK pathways causes activation of FOXO transcription factor, leading to cell cycle arrest and apoptosis in pancreatic cancer. J Mol Signal, 5, 10.
  12. Rungtabnapa P, Nimmannit U, Halim H, et al (2011). Hydrogen peroxide inhibits non-small cell lung cancer cell anoikis through the inhibition of caveolin-1 degradation. Am J Physiol Cell Physiol, 300, C235-45.
  13. Sargiacomo M, Sudol M, Tang Z, et al (1993). Signal transducing molecules and glycosyl-phosphatidylinositol-linked proteins form a caveolin-rich insoluble complex in MDCK cells. J Cell Biol, 122, 789-807.
  14. Kim HP, Wang X, Nakao A, et al (2005). Caveolin-1 expression by means of p38beta mitogen-activated protein kinase mediates the antiproliferative effect of carbon monoxide. Proc Natl Acad Sci U S A, 102, 11319-24.
  15. Kimbro KS, Duschene K, Willard M, et al (2008). A novel gene STYK1/NOK is upregulated in estrogen receptor-alpha negative estrogen receptor-beta positive breast cancer cells following estrogen treatment. Mol Biol Rep, 35, 23-7.
  16. Koleske AJ, Baltimore D, Lisanti MP (1995). Reduction of caveolin and caveolae in oncogenically transformed cells. Proc Natl Acad Sci U S A, 92, 1381-5.
  17. Konduri S, Schwarz RE (2007). Estrogen receptor beta/alpha ratio predicts response of pancreatic cancer cells to estrogens and phytoestrogens. J Surg Res, 140, 55-66.
  18. Krechler T, Horejs J, Ulrych J, et al (2011). Current status of pancreatic cancer diagnosis. Cas Lek Cesk, 150, 587-93.
  19. Lee KB, Byun HJ, Park SH, et al (2012). CYR61 controls p53 and NF-kappaB expression through PI3K/Akt/mTOR pathways in carboplatin-induced ovarian cancer cells. Cancer Lett, 315, 86-95.
  20. Lee SH, Park BJ (2011). p53 activation by blocking Snail: a novel pharmacological strategy for cancer. Curr Pharm Des, 17, 610-17.
  21. Li L, Ren C, Yang G, et al (2009). Caveolin-1 promotes autoregulatory, Akt-mediated induction of cancer-promoting growth factors in prostate cancer cells. Mol Cancer Res, 7, 1781-91.
  22. Li L, Yang G, Ebara S, et al (2001). Caveolin-1 mediates testosterone-stimulated survival/clonal growth and promotes metastatic activities in prostate cancer cells. Cancer Res, 61, 4386-92.
  23. Liu J, Razani B, Tang S, et al (1999). Angiogenesis activators and inhibitors differentially regulate caveolin-1 expression and caveolae formation in vascular endothelial cells. Angiogenesis inhibitors block vascular endothelial growth factor-induced down-regulation of caveolin-1. J Biol Chem, 274, 15781-5.
  24. Liu L, Xu HX, Wang WQ, et al (2013). Cavin-1is essential for the tumor-promoting effect of caveolin-1 and enhances itsprognostic potency in pancreatic cancer. Oncogene. doi: 10.1038/onc.2013.223.
  25. Llaverias G, Vazquez-Carrera M, Sanchez RM, et al (2004). Rosiglitazone upregulates caveolin-1 expression in THP-1 cells through a PPAR-dependent mechanism. J Lipid Res, 45, 2015-24.
  26. Luo G, Long J, Zhang B, et al (2008). Stroma and pancreatic ductal adenocarcinoma: An interaction loop. Biochim Biophys Acta, 1826, 170-8.
  27. Lynch HT, Deters CA, Snyder CL, et al (2005). BRCA1 and pancreatic cancer: pedigree findings and their causal relationships. Cancer Genet Cytogenet, 158, 119-25.
  28. Maier HJ, Schmidt-Strassburger U, Huber MA, et al (2010). NF-kappaB promotes epithelial-mesenchymal transition, migration and invasion of pancreatic carcinoma cells. Cancer Lett, 295, 214-28.
  29. Mathew R (2011). Cell-specific dual role of caveolin-1 in pulmonary hypertension. Pulm Med, 2011, 573432.
  30. Anderson RG (1998). The caveolae membrane system. Annu Rev Biochem, 67, 199-225.
  31. Arbuzova A, Wang L, Wang J, et al (2000). Membrane binding of peptides containing both basic and aromatic residues. Experimental studies with peptides corresponding to the scaffolding region of caveolin and the effector region of MARCKS. Biochemistry-Us, 39, 10330-9.
  32. Bailey KM, Liu J (2008). Caveolin-1 up-regulation during epithelial to mesenchymal transition is mediated by focal adhesion kinase. J Biol Chem, 283, 13714-24.
  33. Boreddy SR, Pramanik KC, Srivastava SK (2011). Pancreatic tumor suppression by benzyl isothiocyanate is associated with inhibition of PI3K/AKT/FOXO pathway. Clin Cancer Res, 17, 1784-95.
  34. Cai T, Wang H, Chen Y, et al (2008). Regulation of caveolin-1 membrane trafficking by the Na/K-ATPase. J Cell Biol, 182, 1153-69.
  35. Casley-Smith JR, Casley-Smith JR (1975). The fine structure of the blood capillaries of some endocrine glands of the hagfish, Eptatretus stouti: implications for the evolution of blood and lymph vessels. Rev Suisse Zool, 82, 35-40.
  36. Chen W, Chen Y, Qin L, et al (2011). Transcription factor Sp1 is essential for the regulation of the porcine caveolin-1 gene. Dna Cell Biol, 30, 491-7.
  37. Collins BM, Davis MJ, Hancock JF, et al (2012). Structure-based reassessment of the caveolin signaling model: do caveolae regulate signaling through caveolin-protein interactions? Dev Cell, 23, 11-20.
  38. Cordes N, Frick S, Brunner TB, et al (2007). Human pancreatic tumor cells are sensitized to ionizing radiation by knockdown of caveolin-1. Oncogene, 26, 6851-62.
  39. Couet J, Li S, Okamoto T, et al (1997). Identification of peptide and protein ligands for the caveolin-scaffolding domain. Implications for the interaction of caveolin with caveolae-associated proteins. J Biol Chem, 272, 6525-33.
  40. Dasari A, Bartholomew JN, Volonte D, et al (2006). Oxidative stress induces premature senescence by stimulating caveolin-1 gene transcription through p38 mitogen-activated protein kinase/Sp1-mediated activation of two GC-rich promoter elements. Cancer Res, 66, 10805-14.
  41. Decker NK, Abdelmoneim SS, Yaqoob U, et al (2008). Nitric oxide regulates tumor cell cross-talk with stromal cells in the tumor microenvironment of the liver. Am J Pathol, 173, 1002-12.
  42. Di Florio A, Adesso L, Pedrotti S, et al (2011). Src kinase activity coordinates cell adhesion and spreading with activation of mammalian target of rapamycin in pancreatic endocrine tumour cells. Endocr Relat Cancer, 18, 541-54.
  43. Diamantidis M, Tsapournas G, Kountouras J, et al (2008). New aspects of regulatory signaling pathways and novel therapies in pancreatic cancer. Curr Mol Med, 8, 12-37.
  44. Dietzen DJ, Hastings WR, Lublin DM (1995). Caveolin is palmitoylated on multiple cysteine residues. Palmitoylation is not necessary for localization of caveolin to caveolae. J Biol Chem, 270, 6838-42.
  45. Dineen SP, Sullivan LA, Beck AW, et al (2008). The Adnectin CT-322 is a novel VEGF receptor 2 inhibitor that decreases tumor burden in an orthotopic mouse model of pancreatic cancer. BMC Cancer, 8, 352.
  46. Eijkelenboom A, Burgering BM (2013). FOXOs: signalling integrators for homeostasis maintenance. Nat Rev Mol Cell Biol, 14, 83-97.
  47. Evans WT, Coyer RL, Sandusky MF, et al (2003). Characterization of membrane rafts isolated from rat sertoli cell cultures: caveolin and flotillin-1 content. J Androl, 24, 812-21.
  48. Ferrara N (2002). VEGF and the quest for tumour angiogenesis factors. Nat Rev Cancer, 2, 795-803.
  49. Forbes A, Wadehra M, Mareninov S, et al (2007). The tetraspan protein EMP2 regulates expression of caveolin-1. J Biol Chem, 282, 26542-51.
  50. Frank PG, Galbiati F, Volonte D, et al (2001). Influence of caveolin-1 on cellular cholesterol efflux mediated by high-density lipoproteins. Am J Physiol Cell Physiol, 280, C1204-14.
  51. Fujimoto T, Kogo H, Nomura R, et al (2000). Isoforms of caveolin-1 and caveolar structure. J Cell Sci, 113, 3509-17.
  52. Glenney JJ (1989). Tyrosine phosphorylation of a 22-kDa protein is correlated with transformation by Rous sarcoma virus. J Biol Chem, 264, 20163-6.
  53. Gough DR, Cotter TG (2011). Hydrogen peroxide: a Jekyll and Hyde signalling molecule. Cell Death Dis, 2, e213.
  54. Grochola LF, Taubert H, Greither T, et al (2011). Elevated transcript levels from the MDM2 P1 promoter and low p53 transcript levels are associated with poor prognosis in human pancreatic ductal adenocarcinoma. Pancreas, 40, 265-70.
  55. Gunther L, Berberat PO, Haga M, et al (2002). Carbon monoxide protects pancreatic beta-cells from apoptosis and improves islet function/survival after transplantation. Diabetes, 51, 994-9.
  56. Gupta S, Sathishkumar S, Ahmed MM (2010). Influence of cell cycle checkpoints and p53 function on the toxicity of temozolomide in human pancreatic cancer cells. Pancreatology, 10, 565-79.
  57. Han F, Zhu HG (2010). Caveolin-1 regulating the invasion and expression of matrix metalloproteinase (MMPs) in pancreatic carcinoma cells. J Surg Res, 159, 443-50.
  58. Hayer A, Stoeber M, Ritz D, et al (2010). Caveolin-1 is ubiquitinated and targeted to intralumenal vesicles in endolysosomes for degradation. J Cell Biol, 191, 615-29.
  59. Hehlgans S, Eke I, Storch K, et al (2009). Caveolin-1 mediated radioresistance of 3D grown pancreatic cancer cells. Radiother Oncol, 92, 362-70.
  60. Huang C, Qiu Z, Wang L, et al (2012). A novel FoxM1-caveolin signaling pathway promotes pancreatic cancer invasion and metastasis. Cancer Res, 72, 655-65.
  61. Huang C, Xie K (2012). Crosstalk of Sp1 and Stat3 signaling in pancreatic cancer pathogenesis. Cytokine Growth Factor Rev, 23, 25-35.
  62. Ikebe M, Kitaura Y, Nakamura M, et al (2009). Lipopolysaccharide (LPS) increases the invasive ability of pancreatic cancer cells through the TLR4/MyD88 signaling pathway. J Surg Oncol, 100, 725-31.
  63. Ju H, Zou R, Venema VJ, et al (1997). Direct interaction of endothelial nitric-oxide synthase and caveolin-1 inhibits synthase activity. J Biol Chem, 272, 18522-5.
  64. Kato K, Hida Y, Miyamoto M, et al (2002). Overexpression of caveolin-1 in esophageal squamous cell carcinoma correlates with lymph node metastasis and pathologic stage. Cancer, 94, 929-33.
  65. Kato T, Miyamoto M, Kato K, et al (2004). Difference of caveolin-1 expression pattern in human lung neoplastic tissue. Atypical adenomatous hyperplasia, adenocarcinoma and squamous cell carcinoma. Cancer Lett, 214, 121-8.
  66. Schwer CI, Stoll P, Rospert S, et al (2013). Carbon monoxide releasing molecule-2 CORM-2 represses global protein synthesis by inhibition of eukaryotic elongation factor eEF2. Int J Biochem Cell Biol, 45, 201-12.
  67. Shi Q, Le X, Abbruzzese JL, et al (2001). Constitutive Sp1 activity is essential for differential constitutive expression of vascular endothelial growth factor in human pancreatic adenocarcinoma. Cancer Res, 61, 4143-54.
  68. Shi S, Yao W, Xu J, et al (2012). Combinational therapy: new hope for pancreatic cancer? Cancer Lett, 317, 127-35.
  69. Shields DJ, Murphy EA, Desgrosellier JS, et al (2011). Oncogenic Ras/Src cooperativity in pancreatic neoplasia. Oncogene, 30, 2123-34.
  70. Siegel R, DeSantis C, Virgo K, et al (2012). Cancer treatment and survivorship statistics. CA Cancer J Clin, 62, 220-41.
  71. Simpkins SA, Hanby AM, Holliday DL, et al (2012). Clinical and functional significance of loss of caveolin-1 expression in breast cancer-associated fibroblasts. J Pathol, 227, 490-8.
  72. Singh RR, Kumar R (2005). Steroid hormone receptor signaling in tumorigenesis. J Cell Biochem, 96, 490-505.
  73. Smart EJ, Graf GA, McNiven MA, et al (1999). Caveolins, liquid-ordered domains, and signal transduction. Mol Cell Biol, 19, 7289-304.
  74. Smart EJ, Ying YS, Conrad PA, et al (1994). Caveolin moves from caveolae to the Golgi apparatus in response to cholesterol oxidation. J Cell Biol, 127, 1185-97.
  75. Sotgia F, Rui H, Bonuccelli G, et al (2006). Caveolin-1, mammary stem cells, and estrogen-dependent breast cancers. Cancer Res, 66, 10647-51.
  76. Sowa G, Pypaert M, Fulton D, et al (2003). The phosphorylation of caveolin-2 on serines 23 and 36 modulates caveolin-1-dependent caveolae formation. Proc Natl Acad Sci U S A, 100, 6511-6.
  77. Steffens S, Schrader AJ, Blasig H, et al (2011). Caveolin 1 protein expression in renal cell carcinoma predicts survival. BMC Urol, 11, 25.
  78. Takeyama Y (2005). Dietary intake as a risk factor for pancreatic cancer in Japan: high cholesterol and low vitamin C diet. J Gastroenterol, 40, 324-5.
  79. Tanase CP, Dima S, Mihai M, et al (2009). Caveolin-1 overexpression correlates with tumour progression markers in pancreatic ductal adenocarcinoma. J Mol Histol, 40, 23-9.
  80. Terris B, Blaveri E, Crnogorac-Jurcevic T, et al (2002). Characterization of gene expression profiles in intraductal papillary-mucinous tumors of the pancreas. Am J Pathol, 160, 1745-54.
  81. Thomas S, Overdevest JB, Nitz MD, et al (2011). Src and caveolin-1 reciprocally regulate metastasis via a common downstream signaling pathway in bladder cancer. Cancer Res, 71, 832-41.
  82. Tiruppathi C, Shimizu J, Miyawaki-Shimizu K, et al (2008). Role of NF-kappaB-dependent caveolin-1 expression in the mechanism of increased endothelial permeability induced by lipopolysaccharide. J Biol Chem, 283, 4210-8.
  83. Valles PG, Manucha W, Carrizo L, et al (2007). Renal caveolin-1 expression in children with unilateral ureteropelvic junction obstruction. Pediatr Nephrol, 22, 237-48.
  84. van den Heuvel AP, Schulze A, Burgering BM (2005). Direct control of caveolin-1 expression by FOXO transcription factors. Biochem J, 385, 795-802.
  85. Vassilieva EV, Ivanov AI, Nusrat A (2009). Flotillin-1 stabilizes caveolin-1 in intestinal epithelial cells. Biochem Biophys Res Commun, 379, 460-5.
  86. Venema VJ, Zou R, Ju H, et al (1997). Caveolin-1 detergent solubility and association with endothelial nitric oxide synthase is modulated by tyrosine phosphorylation. Biochem Biophys Res Commun, 236, 155-61.
  87. Vepa S, Scribner WM, Natarajan V (1997). Activation of protein phosphorylation by oxidants in vascular endothelial cells: identification of tyrosine phosphorylation of caveolin. Free Radic Biol Med, 22, 25-35.
  88. Wadehra M, Goodglick L, Braun J (2004). The tetraspan protein EMP2 modulates the surface expression of caveolins and glycosylphosphatidyl inositol-linked proteins. Mol Biol Cell, 15, 2073-83.
  89. Wang Y, Yu J, Zhan Q (2008). BRCA1 regulates caveolin-1 expression and inhibits cell invasiveness. Biochem Biophys Res Commun, 370, 201-6.
  90. Wu CC, Wang SH, Kuan II, et al (2009). OxLDL upregulates caveolin-1 expression in macrophages: Role for caveolin-1 in the adhesion of oxLDL-treated macrophages to endothelium. J Cell Biochem, 107, 460-72.
  91. Wu D, Terrian DM (2002). Regulation of caveolin-1 expression and secretion by a protein kinase cepsilon signaling pathway in human prostate cancer cells. J Biol Chem, 277, 40449-55.
  92. Yang G, Truong LD, Wheeler TM, et al (1999). Caveolin-1 expression in clinically confined human prostate cancer: a novel prognostic marker. Cancer Res, 59, 5719-23.
  93. Yang N, Ying C, Xu M, et al (2007). High-fat diet up-regulates caveolin-1 expression in aorta of diet-induced obese but not in diet-resistant rats. Cardiovasc Res, 76, 167-74.
  94. Zhu XD, Zhang JB, Zhuang PY, et al (2008). High expression of macrophage colony-stimulating factor in peritumoral liver tissue is associated with poor survival after curative resection of hepatocellular carcinoma. J Clin Oncol, 26, 2707-16.
  95. Zschocke J, Bayatti N, Behl C (2005). Caveolin and GLT-1 gene expression is reciprocally regulated in primary astrocytes: association of GLT-1 with non-caveolar lipid rafts. Glia, 49, 275-87.
  96. Zschocke J, Manthey D, Bayatti N, et al (2003). Functional interaction of estrogen receptor alpha and caveolin isoforms in neuronal SK-N-MC cells. J Steroid Biochem Mol Biol, 84, 167-70.

피인용 문헌

  1. The evaluation of involvement of angiotensin II, its receptors, and androgen receptor in endometrial cancer vol.31, pp.1, 2015,