Presentation Type
Poster
Discipline Track
Translational Science
Abstract Type
Research/Clinical
Abstract
Pancreatic cancer (PanCa) is the third leading cause of cancer-related deaths in the United States. It shows only a marginal survival benefits of 6 months with the available therapeutics. Thus, to understand the biology of PanCa and discovery of new molecular targets will help in designing the new therapeutic strategies for the management of advanced PanCa. Aberrant ribosome biogenesis is the hallmark of many cancers and has been associated with poor prognosis. Cancer cells show significantly high demand of protein synthesis and to meet this demand modify ribosomal machinery at genetic and epigenetic level. The UBTF (upstream binding transcription factor, RNA polymerase I) gene encodes a member of the HMG-box DNA-binding protein family, which plays a critical role in ribosomal RNA (rRNA) transcription. Recent studies provide strong clues of UBTF involvement in cancer cells survival and chemoresistance. However, no study defines its role in pancreatic cancer. Our results demonstrated that UBTF expression was significantly higher in pancreatic tumors than normal pancreatic tissues as analyzed in tissue microarray. We also observed differential overexpression of total and phospho-UBTF in various human PanCa cells compared to normal pancreatic ductal epithelial cells. Next, we generated UBTF knockdown clones of HPAF-II and MiaPaCa-2 cells and characterized by analyzing UBTF and pre-rRNA expression. We observed 80% inhibition of UBTF and pre-rRNA complex expression which indicates the role of UBTF in functioning of RNA Polymerase I (RNA Pol I). kinase array results showed a significant (P<0.01) decrease expression of mutant p53 in UBTF knockdown MiaPaCa-2 cells (express mutant p53). We also observed that targeted inhibition of UBTF sensitizes the effect of gemcitabine and RNA Pol I inhibitors (BMH-21 and CX-5461) in PanCa cells. Targeted knockdown of UBTF significantly (P<0.01) inhibited the growth of pancreatic tumor in orthotopic xenograft mouse model as analyzed by tumor volume and excised tumor weight. We observed decrease expression of various cell proliferative (PCNA and ki67) and ribosome biogenesis markers (UBTF, RPA-194, pre-rRNA) compared to WT HPAF-II cells xenograft tumors. Taken together, our results suggest that UBTF could be developed as a potential molecular target for pancreatic cancer therapy.
Academic/Professional Position
Fellow
Mentor/PI Department
Immunology and Microbiology
Recommended Citation
Ahmad, Mudassier; Alvi, Sahir Sultan; Ahsan, Haider; Bangash, Muhammad; Ramírez-Correa, Genaro A.; Joon Kim, Dae; Chauhan, Subhash C.; and Hafeez, Bilal B., "Translational impact of UBTF in developing new therapeutic strategy for pancreatic cancer treatment" (2024). Research Symposium. 95.
https://scholarworks.utrgv.edu/somrs/2024/posters/95
Included in
Translational impact of UBTF in developing new therapeutic strategy for pancreatic cancer treatment
Pancreatic cancer (PanCa) is the third leading cause of cancer-related deaths in the United States. It shows only a marginal survival benefits of 6 months with the available therapeutics. Thus, to understand the biology of PanCa and discovery of new molecular targets will help in designing the new therapeutic strategies for the management of advanced PanCa. Aberrant ribosome biogenesis is the hallmark of many cancers and has been associated with poor prognosis. Cancer cells show significantly high demand of protein synthesis and to meet this demand modify ribosomal machinery at genetic and epigenetic level. The UBTF (upstream binding transcription factor, RNA polymerase I) gene encodes a member of the HMG-box DNA-binding protein family, which plays a critical role in ribosomal RNA (rRNA) transcription. Recent studies provide strong clues of UBTF involvement in cancer cells survival and chemoresistance. However, no study defines its role in pancreatic cancer. Our results demonstrated that UBTF expression was significantly higher in pancreatic tumors than normal pancreatic tissues as analyzed in tissue microarray. We also observed differential overexpression of total and phospho-UBTF in various human PanCa cells compared to normal pancreatic ductal epithelial cells. Next, we generated UBTF knockdown clones of HPAF-II and MiaPaCa-2 cells and characterized by analyzing UBTF and pre-rRNA expression. We observed 80% inhibition of UBTF and pre-rRNA complex expression which indicates the role of UBTF in functioning of RNA Polymerase I (RNA Pol I). kinase array results showed a significant (P<0.01) decrease expression of mutant p53 in UBTF knockdown MiaPaCa-2 cells (express mutant p53). We also observed that targeted inhibition of UBTF sensitizes the effect of gemcitabine and RNA Pol I inhibitors (BMH-21 and CX-5461) in PanCa cells. Targeted knockdown of UBTF significantly (P<0.01) inhibited the growth of pancreatic tumor in orthotopic xenograft mouse model as analyzed by tumor volume and excised tumor weight. We observed decrease expression of various cell proliferative (PCNA and ki67) and ribosome biogenesis markers (UBTF, RPA-194, pre-rRNA) compared to WT HPAF-II cells xenograft tumors. Taken together, our results suggest that UBTF could be developed as a potential molecular target for pancreatic cancer therapy.