Peroxisome Proliferator Activated Receptor Gamma (PPARγ) Activation by Enterolactone Enhances Endoplasmic Reticulum Stress to Sensitize Anti‐cancer Agents
Authors: De Silva Shanal Franklyn , Yang Xiaolei , Alcorn Jane 
Published: June 2021

The limitations of anticancer drugs bespeak a need for a multi‐target, yet safe approach that effectively thwarts cell survival adaptations. Tumor cells with endoplasmic reticulum (ER) stress evoke an adaptive mechanism, the unfolded protein response, for survival. This has become a promising drug target for tumors that upregulate protein synthesis and therefore depend on continuous protein folding to meet the demand. Clear therapeutic prospects exist for PPARγ inducing natural products given their multi‐target activity. PPARγ, a subfamily of the nuclear receptor superfamily can interfere with proliferation, angiogenesis, and differentiation in various cell types and disfavor carcinogenesis. Flaxseed lignans (FLNs) have putative health benefits and evidence to target key cancer survival pathways.Recent studies in our lab demonstrated safety and tolerability of a FLN‐enriched complex in frail and healthy elderly at pharmacological doses and blood levels of total lignans following chronic daily dosing of the FLN‐enriched complex consistent with ability of lignans to exert pharmacological activity. A transactivation assay and glucose uptake assay revealed enterolactone (ENL) as a potential PPARγ partial agonist. We hypothesize that combination of mammalian lignan ENL with clinically relevant anticancer drugs will cause chronic ER stress and in turn enhance anti‐tumor activity in‐vitro.We concluded/plan several experiments to confirm key targets/changes involved in energy metabolism, reactive oxygen species, ER stress, cell survival, vesicular trafficking, and cytoskeletal dynamics using a battery of in‐vitro assays in cancer cell lines.Lignan ENL modulates cellular energy metabolism markers (Examples: Fatty acid synthase/FASN, Sterol regulatory element‐binding proteins/SREBPs, Insulin induced gene 1/INSIG1, Low density lipoprotein receptor/LDLR, PPARγ, Glucose transporter 1/GLUT1, and Pyruvate kinase muscle isozyme M2/PKM2), and ER stress markers (Examples: Activating transcription factor 4/ATF4, CCAAT‐enhancer‐binding protein homologous protein/CHOP, Growth arrest and DNA damage‐inducible protein 34/GADD34 and Glucose‐regulated protein 58/GRP58). ENL reduced mitochondrial redox function and caused mitochondrial toxicity in‐vitro. Various anticancer drugs in combination with ENL caused significant reduction in cell viability.These findings warrant further investigations to support FLNs' ability to enhance ER stress as the key mechanism involved in the disruption of cellular survival adaptations when combined with anticancer drugs. Lignans are safe and therefore are good candidates for adjuvant/combination therapy that could improve patient longevity and quality of life.Support or Funding InformationSaskatchewan Health Research Foundation (Research Funding), and College of Pharmacy & Nutrition, College of Graduate & Post‐doctoral Studies, and Apotex Canada (Graduate Student Scholarships)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.