Talks
Academic Level (Author 1)
Post-doc
Discipline/Specialty (Author 1)
Cancer and Immunology
Academic Level (Author 2)
Post-doc
Discipline/Specialty (Author 2)
Cancer and Immunology
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Cancer and Immunology
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Faculty
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Medical Student
Academic Level (Author 6)
Post-doc
Academic Level (Author 8)
Faculty
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Cancer and Immunology
Academic Level (Author 9)
Faculty
Discipline/Specialty (Author 9)
Cancer and Immunology
Academic Level (Author 10)
Faculty
Discipline/Specialty (Author 10)
Cancer and Immunology
Discipline Track
Biomedical Science
Abstract
Pancreatic ductal adenocarcinoma is the third leading cause of cancer-related deaths in the United States with limited therapeutic options available. Gemcitabine, a deoxycytidine nucleoside analog is currently considered the most effective therapy for PanCa. However, it shows only a marginal survival benefit of six months. Aberrant ribosome biogenesis occurs in most tumor types. We observed that PanCa cells are addicted to ribosome biogenesis, which supports their highly aggressive metastatic phenotypes. Thus, strategically targeting ribosome biogenesis process could be one of the ideal strategies for the prevention and treatment of PanCa. In this study, we elucidated the molecular mechanisms of POLR1A (RPA194) overexpression and how its targeting along with p53 status impacts RNA polymerase I inhibitor therapy against PanCa. The expression level of RPA194 was significantly elevated in pancreatic tumor tissues when compared with adjacent normal pancreatic tissues. BMH-21 is a potent pharmacological inhibitor of RNA Pol I, which is known to degrade RPA194 protein. Our results demonstrated that BMH-21 can selectively induce apoptosis in various PanCa cells but not in normal pancreatic ductal epithelial cells. We also found that the cytotoxic effect of BMH-21 was dependent on the expression pattern of RPA-194 and p53 status. We further examined the therapeutic efficacy of BMH-21 in orthotopic xenograft mouse models by using two different PanCa cells, AsPC1 which contains non-functional p53 and MIA PaCa-2 which contains functional mutant p53. We observed that BMH-21 significantly inhibited the growth of tumors derived from both cancer cell lines. Interestingly, BMH-21-mediated inhibition of tumor growth was more significant in tumors derived from MIA PaCa-2 cells compared to AsPC1 cells. We next examined the effect of BMH-21 on various ribosome biogenesis components and marker of cell proliferation in excised pancreatic tumor tissues. We observed that inhibition of tumor growth was correlated with RPA194 degradation and decreased expression of Ki67 in BMH-21 treated samples. Taken together, our results strongly demonstrate that BMH-21 is a promising non-toxic agent for the treatment of advanced PanCa and its therapeutic potential depends on suppressing ribosome biogenesis and p53 status in pancreatic tumor.
Presentation Type
Talk
Recommended Citation
Ahmad, Mudassier; Ahsan, Haider; Perez, Carlos; Bangash, Muhammad; Massey, Andrew; Anning, Emmanuel; Tripathi, Manish; Kim, Dae; Chauhan, Subhash C.; and Hafeez, Bilal Bin, "Targeting ribosome biogenesis is a novel approach for the management of pancreatic cancer" (2024). Research Colloquium. 19.
https://scholarworks.utrgv.edu/colloquium/2024/talks/19
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Targeting ribosome biogenesis is a novel approach for the management of pancreatic cancer
Pancreatic ductal adenocarcinoma is the third leading cause of cancer-related deaths in the United States with limited therapeutic options available. Gemcitabine, a deoxycytidine nucleoside analog is currently considered the most effective therapy for PanCa. However, it shows only a marginal survival benefit of six months. Aberrant ribosome biogenesis occurs in most tumor types. We observed that PanCa cells are addicted to ribosome biogenesis, which supports their highly aggressive metastatic phenotypes. Thus, strategically targeting ribosome biogenesis process could be one of the ideal strategies for the prevention and treatment of PanCa. In this study, we elucidated the molecular mechanisms of POLR1A (RPA194) overexpression and how its targeting along with p53 status impacts RNA polymerase I inhibitor therapy against PanCa. The expression level of RPA194 was significantly elevated in pancreatic tumor tissues when compared with adjacent normal pancreatic tissues. BMH-21 is a potent pharmacological inhibitor of RNA Pol I, which is known to degrade RPA194 protein. Our results demonstrated that BMH-21 can selectively induce apoptosis in various PanCa cells but not in normal pancreatic ductal epithelial cells. We also found that the cytotoxic effect of BMH-21 was dependent on the expression pattern of RPA-194 and p53 status. We further examined the therapeutic efficacy of BMH-21 in orthotopic xenograft mouse models by using two different PanCa cells, AsPC1 which contains non-functional p53 and MIA PaCa-2 which contains functional mutant p53. We observed that BMH-21 significantly inhibited the growth of tumors derived from both cancer cell lines. Interestingly, BMH-21-mediated inhibition of tumor growth was more significant in tumors derived from MIA PaCa-2 cells compared to AsPC1 cells. We next examined the effect of BMH-21 on various ribosome biogenesis components and marker of cell proliferation in excised pancreatic tumor tissues. We observed that inhibition of tumor growth was correlated with RPA194 degradation and decreased expression of Ki67 in BMH-21 treated samples. Taken together, our results strongly demonstrate that BMH-21 is a promising non-toxic agent for the treatment of advanced PanCa and its therapeutic potential depends on suppressing ribosome biogenesis and p53 status in pancreatic tumor.