PRSS3/mesotrypsin is a therapeutic target for metastatic prostate cancer

Alexandra Hockla, Erin Miller, Moh'd A. Salameh, John A III Copland, Derek C Radisky, Evette S Radisky

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

PRSS3/mesotrypsin is an atypical isoform of trypsin that has been associated with breast, lung, and pancreatic cancer cell malignancy. In analyses of open source transcriptional microarray data, we find that PRSS3 expression is upregulated in metastatic prostate cancer tissue, and that expression of PRSS3 in primary prostate tumors is prognostic of systemic progression following prostatectomy. Using a mouse orthotopic model with bioluminescent imaging, we show that PRSS3/mesotrypsin is critical for prostate cancer metastasis. Silencing of PRSS3 inhibits anchorage-independent growth of prostate cancer cells in soft agar assays, and suppresses invasiveness in Matrigel transwell assays and three-dimensional (3D) cell culture models. Wefurther show that treatment with recombinant mesotrypsin directly promotes an invasive cellular phenotype in prostate cancer cells and find that these effects are specific and require the proteolytic activity of mesotrypsin, because neither cationic trypsin nor a mesotrypsin mutant lacking activity can drive the invasive phenotype. Finally, we show that a newly developed, potent inhibitor of mesotrypsin activity can suppress prostate cancer cell invasion to a similar extent as PRSS3 gene silencing. This study defines mesotrypsin as an important mediator of prostate cancer progression and metastasis, and suggests that inhibition of mesotrypsin activity may provide a novel modality for prostate cancer treatment.

Original languageEnglish (US)
Pages (from-to)1555-1566
Number of pages12
JournalMolecular Cancer Research
Volume10
Issue number12
DOIs
StatePublished - Dec 2012

Fingerprint

Prostatic Neoplasms
Trypsin
Therapeutics
Neoplasm Metastasis
Phenotype
Gene Silencing
Prostatectomy
Pancreatic Neoplasms
Agar
Prostate
Lung Neoplasms
Neoplasms
Protein Isoforms
Cell Culture Techniques
Breast Neoplasms
Growth

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Oncology

Cite this

PRSS3/mesotrypsin is a therapeutic target for metastatic prostate cancer. / Hockla, Alexandra; Miller, Erin; Salameh, Moh'd A.; Copland, John A III; Radisky, Derek C; Radisky, Evette S.

In: Molecular Cancer Research, Vol. 10, No. 12, 12.2012, p. 1555-1566.

Research output: Contribution to journalArticle

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