Recombinant Lz-8 from Ganoderma lucidum induces endoplasmic reticulum stress-mediated autophagic cell death in SGC-7901 human gastric cancer cells

In Asia, the mushroom of the fungus Ganoderma lucidum has been widely used as a traditional medicine for the past two millennia. The aim of this study was to investigate the anticancer activity of recombinant Lz-8 (rLz-8), a protein belonging to a family of fungal immunomodulatory proteins. We report that rLz-8 induces endoplasmic reticulum (ER) stress-mediated autophagic cell death in the human gastric cancer cell line SGC-7901. Our results show that rLz-8 induces autophagic cell death by aggregating in the ER, triggering ER stress and the ATF4-CHOP pathway. A foreign protein, in the ER rLz-8 causes the activation of the ubiquitine/proteasome ER-associated degradation (ERAD) system. The autophagic arm of this system is then overstimulated by an excessive abundance of rLz-8 and causes the cell's death through an over-autophagic response. We also found that caspase inhibitors do not prevent rLz-8-induced cell death, and therefore the autophagic response induced by rLz-8 is independent of caspase activation.