DNA-PKcs plays role in cancer metastasis through regulation of secreted proteins involved in migration and invasion

Abstract

The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) plays a major role in DNA damage signaling and repair and is also frequently overexpressed in tumor metastasis. We used isogenic cell lines expressing different levels of DNA-PKcs to investigate the role of DNA-PKcs in metastatic development. We found that DNA-PKcs participates in melanoma primary tumor and metastasis development by stimulating angiogenesis, migration and invasion. Comparison of conditioned medium content from DNA-PKcs-proficient and deficient cells reveals that DNA-PKcs controls secretion of at least 103 proteins (including 44 metastasis-associated with FBLN1, SERPINA3, MMP-8, HSPG2 and the inhibitors of matrix metalloproteinases, such as α-2M and TIMP-2). High throughput analysis of secretomes, proteomes and transcriptomes, indicate that DNA-PKcs regulates the secretion of 85 proteins without affecting their gene expression. Our data demonstrate that DNA-PKcs has a pro-metastatic activity via the modification of the tumor microenvironment. This study shows for the first time a direct link between DNA damage repair and cancer metastasis and highlights the importance of DNA-PKcs as a potential target for anti-metastatic treatment.

A four‐gene transcript score to predict metastatic‐lethal progression in men treated for localized prostate cancer: Development and validation studies

“…The basement membrane component fibulin 1 ( FBLN1 ) is suggested to function both as a tumor suppressor and an oncogene. Its role as a tumor suppressor is supported by the fact that FBLN1 was shown to inhibit migration and invasion . Downregulation of FBLN1 in bladder cancer was associated with high‐grade cancer and lower recurrence‐free survival; FBLN1 has also been observed to be downregulated in tumors compared to benign prostate tissue, particularly in tumors with overexpression of ERG .…”

DNA‐PkCS expression in oropharyngeal squamous cell carcinoma: Correlations with human papillomavirus status and recurrence after transoral robotic surgery

“…Previous work supports both DNA repair‐mediated and non‐DNA repair‐mediated roles for DNA‐Pk cs in solid tumors . To determine what mechanisms may be responsible for the association that we observed between high DNA‐Pk CS expression and recurrence in oropharyngeal SCCs, we investigated the impact of DNA‐Pk CS on cell proliferation, therapeutic response, cell migration, and cell invasion using the HPV‐negative HNSCC cell lines UM‐SCC1 and UM‐SCC6 .…”

“…[23][24][25][26] However, rates of distant metastasis are similar between patients with HPV-positive and HPV-negative disease, indicating there exists a subset of HPV-positive oropharyngeal SCC with relatively poor outcomes for which we currently have no predictive markers. 27,28 As DNA-Pk CS is associated with increased metastasis and decreased survival in other cancers, [9][10][11][12][13][14][15] we evaluated DNA-Pk CS expression as a prognostic factor in the HPV-positive oropharyngeal SCC subset using logistic regression modeling. In univariate analysis with a threshold of p <.2, age, adjuvant therapy, and DNA-Pk CS H-score were associated with recurrence (p 5.0859, p 5.0295, and p 5.1828, respectively; Table 2).…”

“…DNA‐Pk CS , along with the Ku70/80 heterodimer, forms the DNA‐Pk complex required for repair of DNA double‐strand breaks via nonhomologous end‐joining, which is the primary pathway involved in repair of radiation‐induced damage . DNA‐Pk also promotes therapeutic resistance, metastasis, and decreased survival in a variety of solid tumors by regulating the activity of transcription factors …”

“…7,8 DNA-Pk also promotes therapeutic resistance, metastasis, and decreased survival in a variety of solid tumors by regulating the activity of transcription factors. [9][10][11][12][13][14][15] The purpose of the current study was to validate the relationship between HPV status and expression of DNA-Pk CS in clinical oropharyngeal SCC samples and to determine the association between DNA-Pk CS expression and patient outcomes. We report decreased DNA-Pk CS protein in HPV-positive compared to HPV-negative oropharyngeal SCCs.…”