PKCδ regulates death receptor 5 expression induced by PS-341 through ATF4-ATF3/CHOP axis in human lung cancer cells

Area of Science:

• Oncology
• Molecular Biology
• Cellular Signaling

Background:

• Bortezomib (PS-341) is an approved proteasome inhibitor for multiple myeloma.
• Previous studies indicated PS-341 induces apoptosis in non-small cell lung cancer (NSCLC) cells via death receptor 5 (DR5).
• The precise molecular mechanisms underlying PS-341-induced DR5 upregulation and apoptosis in NSCLC remain incompletely understood.

Purpose of the Study:

• To elucidate the signaling pathways and molecular mediators involved in PS-341-induced DR5 upregulation and apoptosis in NSCLC.
• To investigate the roles of protein kinase C delta (PKCδ), ribosomal S6 kinase 2 (RSK2), and endoplasmic reticulum (ER) stress in this process.

Main Methods:

• Cellular assays including gene silencing (siRNA) and Western blotting to assess protein expression and phosphorylation.
• Inhibition of specific signaling pathways using kinase inhibitors (e.g., MAP-ERK kinase 1/2 inhibitor).
• Analysis of ER stress markers (BiP, p-eIF2α, IRE1α, ATF4, ATF3, CHOP) and DR5 expression levels following PS-341 treatment.

Main Results:

• PS-341 treatment activated ER stress, evidenced by increased BiP, p-eIF2α, IRE1α, ATF4, ATF3, and CHOP expression.
• DR5 upregulation was dependent on ATF4, ATF3, and CHOP, with ATF4 regulating ATF3/CHOP, and ATF3/CHOP forming a complex to control DR5.
• PKCδ cleavage and activation of ERK/RSK2 signaling were crucial for PS-341-induced DR5 upregulation and apoptosis, with PKCδ regulating ER stress and ERK/RSK2 phosphorylation.

Conclusions:

• PS-341 induces cancer cell apoptosis by upregulating DR5 expression.
• This upregulation is mediated by a novel pathway involving PKCδ, ERK/RSK2 signaling, and ER stress activation.
• The ATF4-ATF3/CHOP axis plays a critical role in translating ER stress signals to DR5 expression, elucidating a key mechanism of bortezomib's anti-cancer effects.