Abstract
Background: Inhibition of ribosome biogenesis has recently emerged as a promising strategy for the treatment of metastatic tumors. The RNA polymerase I inhibitor CX-5461 has shown efficacy in a panel of cancer types and is currently being tested in clinical trials. However, further preclinical studies to unravel molecular mechanisms underlying the activity of this drug are warranted. Methods: In this study, we have investigated the effects of CX-5461 on cell growth and migration of pancreatic cancer cells by the sulforhodamine-B and wound healing assay, respectively. Furthermore, we assessed the expression of epithelial-to-mesenchymal transition (EMT) genes by qRT-PCR, while protein expression of DNA damage marker phospho-H2A.X was studied by Western blot and immunofluorescence. Results: CX-5461 inhibits pancreatic cancer cell growth in the nanomolar range and inhibits the migratory capability of the cells. Additionally, CX-5461 induced expression of EMT factor SNAI1 and caused DNA double-strand breaks as measured by increased expression of phospho-H2A.X. Conclusion: This study demonstrated that CX-5461 is active against pancreatic cancer cells and modulation of EMT factors, as well as increased expression of phospho-H2A.X, support further pre-/clinical investigations, including the analyses of these markers.
Highlights
Pancreatic cancer (PC) is a highly metastatic disease with a poor five-year survival of less than10% [1]
Ribosome biogenesis is a process that is upregulated in cancer, where it contributes to increased protein production facilitating cell proliferation [2]
We show that PC cells are sensitive to the small molecule CX-5461, in a nanomolar range, which is in line with previous studies [5]
Summary
Pancreatic cancer (PC) is a highly metastatic disease with a poor five-year survival of less than10% [1]. Exploiting the ribosome biogenesis pathway [3], and RNA polymerase I (pol I) inhibition for cancer treatment, has shown promising results in recent years [4,5]. Inhibition of ribosome biogenesis has recently emerged as a promising strategy for the treatment of metastatic tumors. Methods: In this study, we have investigated the effects of CX-5461 on cell growth and migration of pancreatic cancer cells by the sulforhodamine-B and wound healing assay, respectively. CX-5461 induced expression of EMT factor SNAI1 and caused DNA double-strand breaks as measured by increased expression of phospho-H2A.X. Conclusion: This study demonstrated that CX-5461 is active against pancreatic cancer cells and modulation of EMT factors, as well as increased expression of phospho-H2A.X, support further pre-/clinical investigations, including the analyses of these markers
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