Clinical significance and novel mechanism of action of kallikrein 6 in glioblastoma

Kristen L. Drucker, Alex R. Paulsen, Caterina Giannini, Paul A. Decker, Sachiko I. Blaber, Michael Blaber, Joon H. Uhm, Brian Patrick O'Neill, Robert Brian Jenkins, Isobel A Scarisbrick

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

BackgroundKallikreins 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.MethodsThe 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.ResultsA 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.ConclusionsTaken 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.

Original languageEnglish (US)
Pages (from-to)305-318
Number of pages14
JournalNeuro-Oncology
Volume15
Issue number3
DOIs
StatePublished - Mar 2013

Fingerprint

Kallikreins
Glioblastoma
Cytotoxins
Survival
temozolomide
Neoplasms
PAR-1 Receptor
Thrombin Receptors
Cell Line
Staurosporine
Astrocytoma
Standard of Care
Cisplatin
Cell Survival
Patient Care
Radiotherapy
RNA
Apoptosis
Pathology

Keywords

  • apoptosis
  • glioma
  • grade IV
  • malignancy
  • temozolomide

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Clinical Neurology

Cite this

Clinical significance and novel mechanism of action of kallikrein 6 in glioblastoma. / Drucker, Kristen L.; Paulsen, Alex R.; Giannini, Caterina; Decker, Paul A.; Blaber, Sachiko I.; Blaber, Michael; Uhm, Joon H.; O'Neill, Brian Patrick; Jenkins, Robert Brian; Scarisbrick, Isobel A.

In: Neuro-Oncology, Vol. 15, No. 3, 03.2013, p. 305-318.

Research output: Contribution to journalArticle

Drucker, Kristen L. ; Paulsen, Alex R. ; Giannini, Caterina ; Decker, Paul A. ; Blaber, Sachiko I. ; Blaber, Michael ; Uhm, Joon H. ; O'Neill, Brian Patrick ; Jenkins, Robert Brian ; Scarisbrick, Isobel A. / Clinical significance and novel mechanism of action of kallikrein 6 in glioblastoma. In: Neuro-Oncology. 2013 ; Vol. 15, No. 3. pp. 305-318.
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AU - Giannini, Caterina

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AU - Blaber, Sachiko I.

AU - Blaber, Michael

AU - Uhm, Joon H.

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N2 - BackgroundKallikreins 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.MethodsThe 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.ResultsA 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.ConclusionsTaken 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.

AB - BackgroundKallikreins 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.MethodsThe 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.ResultsA 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.ConclusionsTaken 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.

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