Biology subjects

Boyle, G. M.

Publications and source records attributed to Boyle, G. M..

3 recordsLinked to original sources

bioRxiv2025

Inhibition of BRN2 in Melanoma Reverses Anoikis Resistance and Sensitizes Cells to Killing by Vemurafenib

Anoikis is an apoptotic cell death program triggered upon detachment from surrounding extracellular structures. However, the ability to evade cell death by anoikis in the presence of apoptosis-inducing stimuli is necessary for the formation of malignant tumors and progression to metastasis. Our findings indicate that the BRN2 (POU3F2) transcription factor is associated with anoikis resistance in melanoma cells. However, the BRN2 signaling cascade driving anoikis resistance remains unknown. Herein, we employed genome-wide CRISPR screens to validate BRN2 as a driver of anoikis resistance. Small molecule inhibition of BRN2 in melanoma cell lines with acquired anoikis resistance resensitized to death by anoikis in ultra-low attachment conditions. Our quantitative mass spectrometry analysis revealed that BRN2 functionally impacts oxidative phosphorylation and mitochondrial activity, whereby probes designed to inhibit BRN2 induced apoptosis and mitochondrial fragmentation through the MAPK and NF-{kappa}B signaling pathways and reduction in PPAR{gamma} expression. Our study suggests that inhibition of BRN2 might allow the targeting of metastatic cells in circulation, and sensitizes cells to BRAF-targeted therapy, improving the prognosis for melanoma patients. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=156 SRC="FIGDIR/small/667908v1_ufig1.gif" ALT="Figure 1"> View larger version (69K): org.highwire.dtl.DTLVardef@12ffd89org.highwire.dtl.DTLVardef@1ae6c8eorg.highwire.dtl.DTLVardef@58e49forg.highwire.dtl.DTLVardef@9b83e_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical Abstract.C_FLOATNO Role of BRN2 in driving anoikis resistance in melanoma. Upon detachment from the extra-cellular matrix (ECM) melanoma cells must evade cell death by anoikis to seed distant metastases. This study expanded the understanding of the role of the BRN2 transcription factor as a driver of resistance to anoikis in melanoma. The use of small molecule inhibitors targeting BRN2 revealed that the transcription factor drives anoikis resistance via the MAPK and NF-{kappa}B signaling pathways, resulting in PPAR{gamma} dysregulation and subsequently driving mitochondrial dysfunction. Green boxes = previously published drivers of anoikis resistance in melanoma. Blue box = changes to mitochondrial function following inhibition of BRN2 as determined by proteomics analysis. C_FIG

cancer biology↗

bioRxiv2022

Aspirin synergizes with regorafenib to reduce growth of colorectal cancer

PurposeRegorafenib is a multi-kinase inhibitor approved for refractory metastatic colorectal cancer. Previous studies have suggested that combining kinase inhibitors with aspirin may improve patient outcomes. We aimed to determine the effects of aspirin and regorafenib combination treatment in preclinical models of colorectal cancer. Experimental DesignSW480, RKO and LIM1215 colorectal cancer cell lines were treated with aspirin and regorafenib to determine effects on proliferation and cytotoxicity. RNA sequencing and Western blotting were performed to explore underlying molecular effects. Aspirin and regorafenib combination treatment was also tested using organoids derived from three human colorectal cancer tissue specimens. For the in vivo study, SW480-derived tumors were established in athymic mice. Tumor volume was measured during treatment with aspirin and regorafenib, followed by immunohistochemical staining for markers of proliferation and apoptosis. ResultsAspirin and regorafenib synergistically inhibited proliferation of colorectal cancer cell lines and patient-derived organoids, irrespective of KRAS or BRAF mutation status. This was associated with inhibition of the PI3K-Akt-mTOR pathway and activation of the AMPK pathway. Aspirin and regorafenib effectively inhibited growth of microsatellite stable KRAS-mutant SW480-derived tumors in vivo. Immunohistochemical staining for Ki67 and cleaved caspase 3 showed that combination treatment elicited a synergistic anti-proliferative effect, in addition to a pro-apoptotic effect that was driven by regorafenib. ConclusionsAspirin and regorafenib demonstrate synergistic anti-proliferative effects in preclinical models of colorectal cancer. This suggests that combining regorafenib with aspirin may be an improved treatment strategy for patients with refractory metastatic colorectal cancer.

cancer biology↗

bioRxiv2018

Kunitz type protease inhibitor EgKI-1 from the canine tapeworm Echinococcus granulosus as a promising anti-cancer therapeutic

EgKI-1, a member of the Kunitz type protease inhibitor family, is highly expressed by the oncosphere of the canine tapeworm Echinococcus granulosus, the stage that is infectious to humans and ungulates, giving rise to a hydatid cyst localized to the liver and other organs. Larval protoscoleces, which develop within the hydatid cyst, have been shown to possess anti-cancer properties, although the precise molecules involved have not been identified. We show that recombinant EgKI-1 inhibits the growth and migration of a range of human cancers including breast, melanoma and cervical cancer cell lines in a dose-dependent manner in vitro without affecting normal cell growth. Furthermore, EgKI-1 treatment arrested the cancer cell growth by disrupting the cell cycle and induced apoptosis of cancer cells in vitro. An in vivo model of triple negative breast cancer (MDA-MB-231) in BALB/c nude mice showed significant tumor growth reduction in EgKI-1-treated mice compared with controls. These findings indicate that EgKI-1 shows promise for future development as an anti-cancer therapeutic.

cancer biology↗