Rosoloactone: A natural diterpenoid inducing apoptosis in human cervical cancer cells through endoplasmic reticulum stress and mitochondrial damage

Natural diterpenoids have been previously reported to induce tumor cell apoptosis. We identified a diterpenoid metabolite as rosoloactone that was isolated from the endophytic fungus Trichothecium roseum and displayed significant antitumor activity in vitro. In this study, we report the antitumor effect of rosoloactone on human cervical cancer HeLa cells and its mechanism of action. Our data indicate that rosoloactone induces strong anti-proliferative and pro-apoptotic effects in human cervical cancer HeLa cells, leads to significant apoptotic morphological characteristics, and increases the number of Annexin V-positive stained cells. These effects were associated with endoplasmic reticulum stress (ERS) and mitochondrial damage. More specifically, rosoloactone caused accumulation of misfolded or unfolded proteins in the ER lumen, leading to excessive ERS, as well as mitochondrial damage followed by release of cytochrome c into the cytosol, activation of caspase-9 and −3, and subsequent activation of mitochondria-mediated apoptosis. Furthermore, the effects of rosoloactone were likely accompanied by marked reactive oxygen species (ROS) production. Altogether our results showed that rosoloactone mediates pro-apoptotic effects in human cervical cancer HeLa cells likely via the activation of ERS-associated apoptosis and the mitochondria-mediated apoptotic pathway.