Anti-proliferation of triple-negative breast cancer cells with physagulide P: ROS/JNK signaling pathway induces apoptosis and autophagic cell death

Abstract

Physagulide P (PP), a new natural compound, was isolated from Physalis angulate L. in our laboratory. In this study, we demonstrated that PP potently suppressed cell proliferation by inducing G2/M phase arrest in MDA-MB-231 and MDA-MB-468 cells. Moreover, PP provoked apoptosis by decreasing the mitochondrial membrane potential and elevating the Bax/Bcl-2 protein expression ratio. The caspase inhibitor Z-VAD-FMK partly restore cell viability, suggesting that apoptosis plays as an important role in the anti-proliferative effect of PP. PP-treated cells also underwent autophagy, as evidenced by the formation of autophagosomes and the accumulation of LC3BII. Furthermore, the knockdown of LC3B reduced PP-induced cytotoxicity, indicating that autophagy played an anticancer effect. PP also induced the generation of reactive oxygen species (ROS) and resulted in c-Jun N-terminal kinases (JNK) activation. Accordingly, JNK siRNA significantly attenuated PP-triggered apoptosis and autophagy, and ROS scavengers almost completely reverse this apoptosis and autophagy. The ROS scavenger also blocked PP-induced G2/M phase arrest and the phosphorylation of JNK. Our results revealed that PP induced G2/M phase arrest, apoptosis and autophagy via the ROS/JNK signaling pathway in MDA-MB-231 and MDA-MB-468 cells. Therefore, PP is a promising candidate for the development of antitumor drugs for the treatment of triple-negative breast cancer.

Oxidative Stress and Endoplasmic Reticulum Stress Are Involved in the Protective Effect of Alpha Lipoic Acid Against Heat Damage in Chicken Testes

“…Usually, HS induces an acute increase in the levels of ROS, which are considered to be strong oxidizers [28]. Meanwhile, antioxidant enzymes, the most important defenders that significantly reduce the toxicity of ROS, have a protective effect against the adverse effects of lipid peroxidation [29]. Nevertheless, antioxidant…”

“…Usually, HS induces an acute increase in the levels of ROS, which are considered to be strong oxidizers [28]. Meanwhile, antioxidant enzymes, the most important defenders that significantly reduce the toxicity of ROS, have a protective effect against the adverse effects of lipid peroxidation [29]. Nevertheless, antioxidant enzymes, including GPx, SOD, and CAT, cannot effectively eliminate the increased amount of ROS due to persistent or severe HS, which induces an imbalance in redox status in vivo, resulting in excessive accumulation of MDA and oxidative damage to the tissue [30,31].…”

JNK signaling in cancer cell survival

“…Bcl‐2 is an important mediator of the activation of autophagy by JNK. The JNK‐induced Bcl‐2 pathway is responsible for the protective role of autophagy in HCC . The dual roles of JNK1‐mediated Bcl‐2 phosphorylation in autophagy are dictated by time‐dependent processes .…”

“…The JNK-induced Bcl-2 pathway is responsible for the protective role of autophagy in HCC. 104,105 The dual roles of JNK1-mediated Bcl-2 phosphorylation in autophagy are dictated by time-dependent processes. 106,107 Rapid Bcl-2 phosphorylation occurs initially to promote cell survival via disrupting the Bcl-2-beclin 1 complex and activating autophagy.…”

The multifaceted role of autophagy in cancer and the microenvironment

“…On the contrary, autophagy may also be a driver of cytotoxic cell death and in this case inhibition of autophagy would inhibit cell death. This type of cell death has been termed autophagic cell death (ACD) and has been reported, eg, for radiation therapy . Thus, depending on the type of cell death inhibition of autophagy may be warranted for combination therapy.…”