title: Clinical significance and novel mechanism of action of kallikrein 6 in glioblastoma.
abstract: BACKGROUND
  Kallikreins have prognostic value in specific malignancies, but few studies have addressed their clinical significance to glioblastoma multiforme (GBM). Kallikrein 6 (KLK6) is of potential high relevance to GBM, since it is upregulated at sites of CNS pathology and linked to reactive astrogliosis. Here we examine the clinical value of KLK6 as a prognostic indicator of GBM patient survival and its activity in promoting resistance to cytotoxic agents.
  
  
  METHODS
  The association between patient survival and levels of KLK6 immunoreactivity were investigated in 60 grade IV astrocytoma tumor specimens. Levels of KLK6 RNA were also evaluated in a separate set of GBM patient tumors (n = 23). Recombinant KLK6 or enforced KLK6 overexpression in GBM cell lines was used to evaluate effects on astrocytoma cell survival.
  
  
  RESULTS
  A range of KLK6 expression was observed across grade IV tumors, with higher levels a poor prognostic indicator of patient survival (P = .02) even after adjusting for gender and Eastern Cooperative Oncology Group performance scores (P = .01). KLK6 reduced the sensitivity of GBM cell lines to cytotoxic agents, including staurosporine and cisplatin, and to the current standard of patient care: radiotherapy or temozolomide alone or in combination. The ability of KLK6 to promote resistance to apoptosis was dependent on activation of the thrombin receptor, protease activated receptor 1.
  
  
  CONCLUSIONS
  Taken together, these results indicate that elevated levels of KLK6 in GBM are likely to promote the resistance of tumor cells to cytotoxic agents and are an indicator of reduced patient postsurgical survival times.
authors: Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, 200 First St., SW., Rochester, MN 55905, USA.
authors: Kristen L
authors: KL
authors: Drucker
authors: Alex R
authors: AR
authors: Paulsen
authors: Caterina
authors: C
authors: Giannini
authors: Paul A
authors: PA
authors: Decker
authors: Sachiko I
authors: SI
authors: Blaber
authors: Michael
authors: M
authors: Blaber
authors: Joon H
authors: JH
authors: Uhm
authors: Brian P
authors: BP
authors: O'Neill
authors: Robert B
authors: RB
authors: Jenkins
authors: Isobel A
authors: IA
authors: Scarisbrick
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D006801:Humans; D007610:Kallikreins / Q000235:genetics / Q000378:metabolism*; D060787:Neoplasm Grading; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019311:Staurosporine / Q000494:pharmacology; D015996:Survival Rate; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D011994:Recombinant Proteins; C103551:KLK6 protein, human; D007610:Kallikreins; D019311:Staurosporine; D002945:Cisplatin