Ovarian cancer is one of the most lethal gynecologic cancers. The standard therapy for ovarian cancer has been the same for the past two decades, a combination treatment of platinum with paclitaxel. Recently, the FDA approved three new therapeutic drugs, two poly (ADP-ribose) polymerase inhibitors (olaparib and niraparib) and one vascular endothelial growth factor inhibitor (bevacizumab) as maintenance therapies for ovarian cancer. In this review, we summarize the resistance mechanisms for conventional platinum-based chemotherapy and for the newly FDA-approved drugs.
The adipokine chemerin may support blood pressure, evidenced by a fall in mean arterial pressure after whole body antisense oligonucleotide (ASO)-mediated knockdown of chemerin protein in rat models of normal and elevated blood pressure. While the liver is the greatest contributor of circulating chemerin, liver-specific ASOs that abolished hepatic-derived chemerin did not change blood pressure. Thus, other sites must produce the chemerin that supports blood pressure. We hypothesize the vasculature as a source of chemerin independent of the liver that supports arterial tone. RNAScope®, PCR, Western analyses, ASOs, isometric contractility, and radiotelemetry were used in the Dahl salt sensitive (SS) rat (male and female) on a normal diet. Rarres2 mRNA was detected in the smooth muscle, adventitia, and perivascular adipose tissue of the thoracic aorta. Chemerin protein was detected immunohistochemically in the endothelium, smooth muscle cells, adventitia, and perivascular adipose tissue. Chemerin colocalized with the vascular smooth muscle marker a-actin and the adipocyte marker perilipin. Importantly, chemerin protein in the thoracic aorta was not reduced when liver-derived chemerin was abolished by a liver-specific ASO against chemerin. Chemerin protein was similarly absent in arteries from a newly created global chemerin knockout in Dahl SS rats. Inhibition of the receptor Chemerin1 by the receptor antagonist CCX832 resulted in loss of vascular tone that supports potential contributions of chemerin by both PVAT and the media. These data suggest that vessel-derived chemerin may support vascular tone locally through constitutive activation of Chemerin1. This posits chemerin as a potential therapeutic target in blood pressure regulation.
The VACM‐1/Cul5 protein is a part of the ubiquitin E3 ligase system responsible for ubiquitin‐dependent protein degradation. The VACM‐1/Cul5 dependent E3 ligase decreases cellular proliferation, and lack of regulation in this pathway can lead to cancer. The CRISPR‐Cas9 system is a bacterial immune system that functions by targeting specific sequences of DNA. It can be programmed to target genes of interest and enables specific gene editing in eukaryotic cells. This system was previously used to knockout VACM‐1/Cul5 in a T47D breast cancer cell line and in a human umbilical vein endothelial cell line (HUVEC). The immunostaining results of control and CRISPR‐transfected HUVEC and T47D cells indicate knockout of VACM‐1. Confirmation of the knockout in the T47D cell line was achieved through a T7 Endonuclease 1 mismatch cleavage assay, proving a homozygous mutation of both alleles. AlamarBlue® growth assays in the T47D cell line and Matrigel® growth assays in the HUVEC cell lines show that VACM‐1/Cul5 knockouts in both cell lines increase proliferation. Together, these results suggest that VACM‐1/CUL5 is an important regulator of cellular growth in breast cancer and endothelial cells. Our current work focuses on determining the effects of the VACM‐1/Cul5 knockout on T47D and HUVEC cell signaling pathways.Support or Funding InformationThis work was supported by the Sherman Fairchild Research Grant to S. Bonema and Biology Department.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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