title: Identification of a novel TGFβ/PKA signaling transduceome in mediating control of cell survival and metastasis in colon cancer.
abstract: BACKGROUND
  Understanding drivers for metastasis in human cancer is important for potential development of therapies to treat metastases. The role of loss of TGFβ tumor suppressor activities in the metastatic process is essentially unknown.
  
  
  RESULTS
  Utilizing in vitro and in vivo techniques, we have shown that loss of TGFβ tumor suppressor signaling is necessary to allow the last step of the metastatic process - colonization of the metastatic site. This work demonstrates for the first time that TGFβ receptor reconstitution leads to decreased metastatic colonization. Moreover, we have identified a novel TGFβ/PKA tumor suppressor pathway that acts directly on a known cell survival mechanism that responds to stress with the survivin/XIAP dependent inhibition of caspases that effect apoptosis. The linkage between the TGFβ/PKA transduceome signaling and control of metastasis through induction of cell death was shown by TGFβ receptor restoration with reactivation of the TGFβ/PKA pathway in receptor deficient metastatic colon cancer cells leading to control of aberrant cell survival.
  
  
  CONCLUSIONS
  This work impacts our understanding of the possible mechanisms that are critical to the growth and maintenance of metastases as well as understanding of a novel TGFβ function as a metastatic suppressor. These results raise the possibility that regeneration of attenuated TGFβ signaling would be an effective target in the treatment of metastasis. Our work indicates the clinical potential for developing anti-metastasis therapy based on inhibition of this very important aberrant cell survival mechanism by the multifaceted TGFβ/PKA transduceome induced pathway. Development of effective treatments for metastatic disease is a pressing need since metastases are the major cause of death in solid tumors.
authors.affiliation: Eppley Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Sanjib
authors.initials: S
authors.lastname: Chowdhury
authors.forename: Gillian M
authors.initials: GM
authors.lastname: Howell
authors.forename: Ashwani
authors.initials: A
authors.lastname: Rajput
authors.forename: Carol A
authors.initials: CA
authors.lastname: Teggart
authors.forename: Lisa E
authors.initials: LE
authors.lastname: Brattain
authors.forename: Hannah R
authors.initials: HR
authors.lastname: Weber
authors.forename: Aparajita
authors.initials: A
authors.lastname: Chowdhury
authors.forename: Michael G
authors.initials: MG
authors.lastname: Brattain
mesh_terms: D000818:Animals; D002470:Cell Survival; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008954:Models, Biological; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D016212:Transforming Growth Factor beta; D017868:Cyclic AMP-Dependent Protein Kinases