Title; Tri-2-Hydroxyarachidonein Induces Cytocidal Autophagy in Pancreatic Ductal Adenocarcinoma Cancer Cell Models.
Journal; Frontiers in Physiology. Section; Lipid and Fatty Acid Research
Date; 2022 Jan 20;12:782525. doi: 10.3389/fphys.2021.782525
Authors; Laboratory of Molecular Cell Biomedicine, Department of Biology, University of the Balearic Islands, Palma de Mallorca (Spain)
and Laminar Pharmaceuticals, Department of R&D, Palma de Mallorca (Spain)
Abstract; Cell proliferation in pancreatic cancer is determined by a complex network of signaling pathways. Despite the extensive understanding of these protein-mediated signaling processes, there are no significant drug discoveries that could considerably improve a patient’s survival. However, the recent understanding of lipid-mediated signaling gives a new perspective on the control of the physiological state of pancreatic cells. Lipid signaling plays a major role in the induction of cytocidal autophagy and can be exploited using synthetic lipids to induce cell death in pancreatic cancer cells. In this work, we studied the activity of a synthetic lipid, tri-2-hydroxyarachidonein (TGM4), which is a triacylglycerol mimetic that contains three acyl moieties with four double bonds each, on cellular and in vivo models of pancreatic cancer. We demonstrated that TGM4 inhibited proliferation of Mia-PaCa-2 (human pancreatic carcinoma) and PANC-1 (human pancreatic carcinoma of ductal cells) in in vitro models and in an in vivo xenograft model of Mia-PaCa-2 cells. In vitro studies demonstrated that TGM4 induced cell growth inhibition paralleled with an increased expression of PARP and CHOP proteins together with the presence of sub-G0 cell cycle events, indicating cell death. This cytocidal effect was associated with elevated ER stress or autophagy markers such as BIP, LC3B, and DHFR. In addition, TGM4 activated peroxisome proliferator-activated receptor gamma (PPAR-γ), which induced elevated levels of p-AKT and downregulation of p-c-Jun. We conclude that TGM4 induced pancreatic cell death by activation of cytocidal autophagy. This work highlights the importance of lipid signaling in cancer and the use of synthetic lipid structures as novel and potential approaches to treat pancreatic cancer and other neoplasias.
Funding; This research was funded by grants from the Ministerio de Economía y Competitividad (PE: RTC-2015-3542, RTC-2015-4094, and RTC2019-007399-1, cofinanced by FEDER funds) and by the Govern de les Illes Balears and European Social Fund (Grants ES01/TCAI/53_2016, PROCOE/5/2017, ES01/TCAI/21_2017, and ES01/TCAI/24_2018). This work was also supported in part by the European Commission (PE: H2020 Framework Programme Project CLINGLIO 755179). JF-D was supported by an Industry Doctorate from the Govern de les Illes Balears and European Social Fund (FPI/1981/2016). RB-G was supported by an Industry Doctorate contract from the Spanish Ministerio de Economía y Competitividad (DI-14-06701). JC was supported by an Industry Doctorate from the Govern de les Illes Balears and European Social Fund (FPI_063_2020). VL was a recipient of a Torres-Quevedo research contract from the Spanish Ministerio de Economía y Competitividad and the European Social Fund “Investing in your future” (PTQ-17-09056).
The compound, tri-2-hydroxy-eicosatetra (5E,8E,11E,14E) enoine (also tri-2-hydroxyarachidonein or TGM4; Figure 1), was kindly provided by Laminar Pharmaceuticals (Palma, Spain).