Polychlorinated biphenyl quinone-induced signaling transition from autophagy to apoptosis is regulated by HMGB1 and p53 in human hepatoma HepG2 cells.

Abstract

Autophagy, which works to remove stress and maintain cellular homeostasis, is usually considered a "pro-survival" signal. Contrarily, apoptosis is programmed "pro-death" machinery. Polychlorinated biphenyls (PCBs) are a group of ubiquitous industrial pollutants. Our previous studies illustrated that a PCB quinone metabolite, PCB29-pQ, elicited both autophagy and apoptosis. However, the signaling underlying the autophagy and apoptosis cross-talk has not been characterized. Here, we found that PCB29-pQ-induced autophagy mainly occurred at a lower concentration (5 μM), while apoptosis mostly arose at a higher concentration (15 μM) in HepG2 cells. Next, we demonstrated the elevation of intracellular calcium levels and calpain activity with PCB29-pQ treatment; however, the unaffected subcellular location of truncated ATG5 and Beclin1 suggested the irrelevance of calpain towards the autophagy-to-apoptosis signaling shift. HMGB1 and p53 both serve as transcription factors that play crucial roles in the regulation of PCB29-pQ-induced autophagy and apoptosis. PCB29-pQ not only enhanced the expression of HMGB1 and p53 but also promoted their binding and cytosolic translocation. Interestingly, HMGB1 rather than p53 plays a primary role in 5 μM of PCB29-pQ-induced autophagy in the nucleus; however, p53 promoted apoptosis to a great extent in the cytosol at the dose of 15 μM PCB29-pQ. Together, HMGB1 and p53 provided a subtle balance between autophagy and apoptosis, thus determining the fate of PCB29-pQ-treated cells.

• Authors: Qiong Shi, Yawen Wang, Wenjing Dong, Erqun Song, Yang Song
• Journal: Toxicology letters (Toxicol Lett) Vol. 306 Pg. 25-34 (May 15 2019) ISSN: 1879-3169 [Electronic] Netherlands
• PMID: 30742880 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 Elsevier B.V. All rights reserved.

Chemical References

• Environmental Pollutants
• HMGB1 Protein
• HMGB1 protein, human
• Quinones
• RNA, Small Interfering
• TP53 protein, human
• Tumor Suppressor Protein p53
• Polychlorinated Biphenyls
• Calpain
• Calcium

Topics

• Apoptosis (drug effects)
• Autophagy (drug effects)
• Calcium (metabolism)
• Calpain (metabolism)
• Cell Survival (drug effects)
• Environmental Pollutants (toxicity)
• HMGB1 Protein (metabolism)
• Hep G2 Cells
• Humans
• Polychlorinated Biphenyls (toxicity)
• Protein Transport (drug effects)
• Quinones (toxicity)
• RNA, Small Interfering (pharmacology)
• Signal Transduction (drug effects)
• Tumor Suppressor Protein p53 (metabolism)