The Role of PAF1/PD2 in Inducing Drug Resistance In Pancreatic Cancer Cells

Pancreatic cancer is a highly aggressive human cancer and the third leading cause of death due to cancer. Cancer stems cells (CSC) are a small population of cancer cells that mediate tumorigenesis, metastasis, and resistance to standard treatments. By specifically identifying and targeting CSC maintenance genes, the efficiency of treatment modalities can be improved. PAF1 (RNA Polymerase II-Associated Factor 1), also known as PD2 (Pancreatic Differentiation 2) maintains pluripotency of stem cells and is a marker of pancreatic cancer stem cells. It is upregulated in poorly differentiated pancreatic cancer cells. Gemcitabine is a novel deoxycytidine analogue which has been developed as an anticancer therapy. It is widely used as a chemotherapeutic agent and is presently the most effective agent against pancreatic cancer. Our project aimed at understanding the role of PAF1/PD2 in the maintenance of pancreatic cancer stem cells and its contribution to gemcitabine resistance. Immunohistochemistry and Bioinformatics analysis showed increased PAF1 expression in PDAC tumor samples. Through various experimental methods, it was shown that gemcitabine increases the expression of PAF1/PD2 and CSC markers and that the loss of PAF1/PD2 influences the maintenance of PC cells and sensitizes the cells to gemcitabine. The impact of PAF1/PD2 on gemcitabine resistance and CSC marker expression and on human pancreatic tumor samples was also studied. It was concluded that PAF1/PD2 are overexpressed in pancreatic tumor cells, increased expression of PAF1/PD2 is associated with gemcitabine resistance in pancreatic cancer cells, the knockdown of PAF1/PD2 leads to a significant reduction in expression of CSC markers and pancreatic tumorigenesis, and human pancreatic tumor samples showed increased expression of PAF1/PD2. Additionally, altered expression of PAF1/PD2 has prognostic relevance to pancreatic cancer patient survival.https://digitalcommons.unmc.edu/surp2021/1020/thumbnail.jp

Direct mass measurements beyond the proton drip-line

First on-line mass measurements were performed at the SHIPTRAP Penning trap mass spectrometer. The masses of 18 neutron-deficient isotopes in the terbium-to-thulium region produced in fusion-evaporation reactions were determined with relative uncertainties of about $7\cdot 10^{-8}$, nine of them for the first time. Four nuclides ($^{144, 145}$Ho and $^{147, 148}$Tm) were found to be proton-unbound. The implication of the results on the location of the proton drip-line is discussed by analyzing the one-proton separation energies

Position-sensitive ion detection in precision Penning trap mass spectrometry

A commercial, position-sensitive ion detector was used for the first time for the time-of-flight ion-cyclotron resonance detection technique in Penning trap mass spectrometry. In this work, the characteristics of the detector and its implementation in a Penning trap mass spectrometer will be presented. In addition, simulations and experimental studies concerning the observation of ions ejected from a Penning trap are described. This will allow for a precise monitoring of the state of ion motion in the trap.Comment: 20 pages, 13 figure

Blocking c-MET/ERBB1 Axis Prevents Brain Metastasis in ERBB2+ Breast Cancer

Brain metastasis (BrM) remains a significant cause of cancer-related mortality in epidermal growth factor receptor 2-positive (ERBB2+) breast cancer (BC) patients. We proposed here that a combination treatment of irreversible tyrosine kinase inhibitor neratinib (NER) and the c-MET inhibitor cabozantinib (CBZ) could prevent brain metastasis. To address this, we first tested the combination treatment of NER and CBZ in the brain-seeking ERBB2+ cell lines SKBrM3 and JIMT-1-BR3, and in ERBB2+ organoids that expressed the c-MET/ERBB1 axis. Next, we developed and characterized an orthotopic mouse model of spontaneous BrM and evaluated the therapeutic effect of CBZ and NER in vivo. The combination treatment of NER and CBZ significantly inhibited proliferation and migration in ERBB2+ cell lines and reduced the organoid growth in vitro. Mechanistically, the combination treatment of NER and CBZ substantially inhibited ERK activation downstream of the c-MET/ERBB1 axis. Orthotopically implanted SKBrM3+ cells formed primary tumor in the mammary fat pad and spontaneously metastasized to the brain and other distant organs. Combination treatment with NER and CBZ inhibited primary tumor growth and predominantly prevented BrM. In conclusion, the orthotopic model of spontaneous BrM is clinically relevant, and the combination therapy of NER and CBZ might be a useful approach to prevent BrM in BC

The Current Landscape of Antibody-based Therapies in Solid Malignancies

Over the past three decades, monoclonal antibodies (mAbs) have revolutionized the landscape of cancer therapy. Still, this benefit remains restricted to a small proportion of patients due to moderate response rates and resistance emergence. The field has started to embrace better mAb-based formats with advancements in molecular and protein engineering technologies. The development of a therapeutic mAb with long-lasting clinical impact demands a prodigious understanding of target antigen, effective mechanism of action, gene engineering technologies, complex interplay between tumor and host immune system, and biomarkers for prediction of clinical response. This review discusses the various approaches used by mAbs for tumor targeting and mechanisms of therapeutic resistance that is not only caused by the heterogeneity of tumor antigen, but also the resistance imposed by tumor microenvironment (TME), including inefficient delivery to the tumor, alteration of effector functions in the TME, and Fc-gamma receptor expression diversity and polymorphism. Further, this article provides a perspective on potential strategies to overcome these barriers and how diagnostic and prognostic biomarkers are being used in predicting response to mAb-based therapies. Overall, understanding these interdependent parameters can improve the current mAb-based formulations and develop novel mAb-based therapeutics for achieving durable clinical outcomes in a large subset of patients

Elevated PAF1-RAD52 Axis Confers Chemoresistance to Human Cancers

Cisplatin- and gemcitabine-based chemotherapeutics represent a mainstay of cancer therapy for most solid tumors; however, resistance limits their curative potential. Here, we identify RNA polymerase II-associated factor 1 (PAF1) as a common driver of cisplatin and gemcitabine resistance in human cancers (ovarian, lung, and pancreas). Mechanistically, cisplatin- and gemcitabine-resistant cells show enhanced DNA repair, which is inhibited by PAF1 silencing. We demonstrate an increased interaction of PAF1 with RAD52 in resistant cells. Targeting the PAF1 and RAD52 axis combined with cisplatin or gemcitabine strongly diminishes the survival potential of resistant cells. Overall, this study shows clinical evidence that the expression of PAF1 contributes to chemotherapy resistance and worse clinical outcome for lethal cancers

The radiosensitizing effect of doranidazole on human colorectal cancer cells exposed to high doses of irradiation

<p>Abstract</p> <p>Background</p> <p>This paper investigates the effects of a new radiosensitizer, doranidazole, and enhancing irradiation on colorectal cancer cells.</p> <p>Methods</p> <p>The radiosensitizing effect of doranidazole was determined using colony formation and propidium iodide (PI) assays to measure cell growth inhibition and the cell killing effect of human colorectal cancer cell lines exposed to high doses of γ-ray irradiation under hypoxic conditions <it>in vitro</it>. Fluorescence staining and cell migration assays were also used to assess the radiosensitizing effect.</p> <p>Results</p> <p>Cell proliferation evaluated by clonogenic survival curves was significantly inhibited by 5 mmol/L doranidazole, particularly at doses ranging from 10 to 30 Gy of irradiation. The radiosensitizing effect of doranidazole on colorectal cancer cells occurs in a time- and dose-dependent manner. Doranidazole also inhibited the mobility of cell invasion and migration.</p> <p>Conclusion</p> <p>Doranidazole can enhance the killing effect and the cell growth inhibition of colorectal cancer after high-dose irradiation in a time and dose-dependent manner.</p