Oncogenic KRas reprograms pancreatic ductal adenocarcinoma (PDAC) cells to states which are highly resistant to apoptosis. Thus, a major preclinical goal is to identify effective strategies for killing PDAC cells. Artesunate (ART) is an anti-malarial that specifically induces programmed cell death in different cancer cell types, in a manner initiated by reactive oxygen species (ROS)-generation. In this study we demonstrate that ART specifically induced ROS- and lysosomal iron-dependent cell death in PDAC cell lines. Highest cytotoxicity was obtained in PDAC cell lines with constitutively-active KRas, and ART did not affect non-neoplastic human pancreatic ductal epithelial (HPDE) cells. We determined that ART did not induce apoptosis or necroptosis. Instead, ART induced ferroptosis, a recently described mode of ROS- and iron-dependent programmed necrosis which can be activated in Ras-transformed cells. Co-treatment with the ferroptosis inhibitor ferrostatin-1 blocked ART-induced lipid peroxidation and cell death, and increased long-term cell survival and proliferation. Importantly, analysis of PDAC patient mRNA expression indicates a dependency on antioxidant homeostasis and increased sensitivity to free intracellular iron, both of which correlate with Ras-driven sensitivity to ferroptosis. Overall, our findings suggest that ART activation of ferroptosis is an effective, novel pathway for killing PDAC cells.
The L1 cell adhesion molecule (L1CAM) plays a major role in the development of the nervous system and in the malignancy of human tumors. In terms of biological function, L1CAM comes along in two different flavors: (1) a static function as a cell adhesion molecule that acts as a glue between cells; (2) a motility promoting function that drives cell migration during neural development and supports metastasis of human cancers. Important factors that contribute to the switch in the functional mode of L1CAM are: (1) the cleavage from the cell surface by membrane proximal proteolysis and (2) the ability to change binding partners and engage in L1CAM-integrin binding. Recent studies have shown that the cleavage of L1CAM by metalloproteinases and the binding of L1CAM to integrins via its RGD-motif in the sixth Ig-domain activate signaling pathways distinct from the ones elicited by homophilic binding. Here we highlight important features of L1CAM proteolysis and the signaling of L1CAM via integrin engagement. The novel insights into L1CAM downstream signaling and its regulation during tumor progression and epithelial-mesenchymal transition (EMT) will lead to a better understanding of the dualistic role of L1CAM as a cell adhesion and/or motility promoting cell surface molecule.
Background:The targeting of cancer stem cells by monoclonal antibodies offers new options for therapy. CD24 is a glycosylphosphatidylinositol-anchored membrane protein with a small protein core and a high level of glycosylation. It is overexpressed in many human carcinomas and is correlated with poor prognosis. CD24 is a marker for pancreatic and ovarian cancer stem cells, whereas breast cancer stem cells are negative for CD24. In cancer cell lines, changes of CD24 expression can alter cellular properties in vitro and tumour growth in vivo. We have shown before that monotherapy with monoclonal antibody (mAb) SWA11 to CD24 effectively retarded tumour growth in xenotransplanted mice.Methods:Here, we have investigated in more detail the molecular mechanisms of mAb SWA11 therapeutic effects in A549 lung and SKOV3ip ovarian carcinoma models in scid/beige and CD1 mice, respectively. We focused on anti-proliferative, pro-apoptotic, anti-angiogenic and microenvironmental effects of SWA11 mAb treatment.Results:We find that CD24 targeting is associated with changes in tumour cell proliferation and angiogenesis. The treatment lead to increased infiltration of tumour tissues with immune cells suggesting involvement of ADCC. We found that SWA11 mAb treatment strongly altered the intratumoural cytokine microenvironment. The addition of SWA11 mAb to gemcitabine treatment strongly potentiated its anti-cancer efficacy in A549 lung cancer model.Conclusion:Our data demonstrate that targeting of CD24 could be beneficial for the anti-cancer treatment combined with standard chemotherapy regimes.
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