title: Targeting protein tyrosine kinase 6 enhances apoptosis of colon cancer cells following DNA damage.
abstract: Protein tyrosine kinase 6 (PTK6) is an intracellular tyrosine kinase that has distinct functions in normal epithelia and cancer. It is expressed primarily in nondividing epithelial cells in the normal intestine, where it promotes differentiation. However, after DNA damage, PTK6 is induced in proliferating progenitor cells, where it contributes to apoptosis. We examined links between PTK6 and the tumor suppressor p53 in the isogenic p53(+/+) and p53(-/-) HCT116 colon tumor cell lines. We found that p53 promotes expression of PTK6 in HCT116 cells, and short hairpin RNA-mediated knockdown of PTK6 leads to reduced induction of the cyclin-dependent kinase inhibitor p21. Knockdown of PTK6 enhances apoptosis in HCT116 cells with wild-type p53, following treatment of cells with γ-radiation, doxorubicin, or 5-fluorouracil. No differences in the activation of AKT, ERK1/2, or ERK5, known PTK6-regulated prosurvival signaling proteins, were detected. However, activity of STAT3, a PTK6 substrate, was impaired in cells with knockdown of PTK6 following DNA damage. In contrast to its role in the normal epithelium following DNA damage, PTK6 promotes survival of cancer cells with wild-type p53 by promoting p21 expression and STAT3 activation. Targeting PTK6 in combination with use of chemotherapeutic drugs or radiation may enhance death of colon tumor cells with wild-type p53.
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Illinois College of Medicine, M/C 669, 900 South Ashland Avenue, Chicago, IL 60607, USA.
authors.forename: Jessica J
authors.initials: JJ
authors.lastname: Gierut
authors.forename: Priya S
authors.initials: PS
authors.lastname: Mathur
authors.forename: Wenjun
authors.initials: W
authors.lastname: Bie
authors.forename: Jin
authors.initials: J
authors.lastname: Han
authors.forename: Angela L
authors.initials: AL
authors.lastname: Tyner
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000473:pathology*; D004249:DNA Damage; D005720:Gamma Rays; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D009363:Neoplasm Proteins / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; D011505:Protein-Tyrosine Kinases; C088375:PTK6 protein, human