Naphthoquinone Derivative PPE8 Induces Endoplasmic Reticulum Stress in p53 Null H1299 Cells

الملخص EN

Endoplasmic reticulum (ER) plays a key role in synthesizing secretory proteins and sensing signal function in eukaryotic cells.

Responding to calcium disturbance, oxidation state change, or pharmacological agents, ER transmembrane protein, inositol-regulating enzyme 1 (IRE1), senses the stress and triggers downstream signals.

Glucose-regulated protein 78 (GRP78) dissociates from IRE1 to assist protein folding and guard against cell death.

In prolonged ER stress, IRE1 recruits and activates apoptosis signal-regulating kinase 1 (ASK1) as well as downstream JNK for cell death.

Naphthoquinones are widespread natural phenolic compounds.

Vitamin K3, a derivative of naphthoquinone, inhibits variant tumor cell growth via oxygen uptake and oxygen stress.

We synthesized a novel naphthoquinone derivative PPE8 and evaluated capacity to induce ER stress in p53 null H1299 and p53 wild-type A549 cells.

In H1299 cells, PPE8 induced ER enlargement, GRP78 expression, and transient IER1 activation.

Activated IRE1 recruited ASK1 for downstream JNK phosphorylation.

IRE1 knockdown by siRNA attenuated PPE8-induced JNK phosphorylation and cytotoxicity.

Prolonged JNK phosphorylation may be involved in PPE8-induced cytotoxicity.

Such results did not arise in A549 cells, but p53 knockdown by siRNA restored PPE8-induced GRP78 expression and JNK phosphorylation.

We offer a novel compound to induce ER stress and cytotoxicity in p53-deficient cancer cells, presenting an opportunity for treatment.