Camptothecin Inhibits Neddylation to Activate the Protective Autophagy Through NF-κB/AMPK/mTOR/ULK1 Axis in Human Esophageal Cancer Cells.

Lijun Jia,Wenjuan Zhang,Junqian Zhang,Shiwen Wang,Yanyu Jiang,Lihui Li,Yongqing Heng,Yupei Liang

doi:10.3389/fonc.2021.671180

Abstract

The neddylation pathway is overactivated in esophageal cancer. Our previous studies indicated that inactivation of neddylation by the NAE inhibitor induced apoptosis and autophagy in cancer cells. Camptothecin (CPT), a well-known anticancer agent, could induce apoptosis and autophagy in cancer cells. However, whether CPT could affect the neddylation pathway and the molecular mechanisms of CPT-induced autophagy in esophageal cancer remains elusive. We found that CPT induced apoptosis and autophagy in esophageal cancer. Mechanistically, CPT inhibited the activity of neddylation and induced the accumulation of p-IkBa to block NF-κB pathway. Furthermore, CPT induced the generation of ROS to modulate the AMPK/mTOR/ULK1 axis to finally promote protective autophagy. In our study, we elucidate a novel mechanism of the NF-κB/AMPK/mTOR/ULK1 pathway in CPT-induced protective autophagy in esophageal cancer cells, which provides a sound rationale for combinational anti-ESCC therapy with CPT and inhibition AMPK/ULK1 pathway.

Highlights

Post-translational modification of proteins plays crucial roles in the regulation of tumorigenesis and tumor progression
These results convincingly demonstrated that CPT induced autophagy in esophageal cancer cells
These results convincingly demonstrated that CPT inhibited cell proliferation and induced apoptosis in esophageal cancer cells

Summary

Introduction

Post-translational modification of proteins plays crucial roles in the regulation of tumorigenesis and tumor progression. Protein neddylation is an important post-translational modification that conjugates the ubiquitin-like molecule NEDD8 (neuronal precursor cell-expressed developmentally downregulated protein 8) to substrate proteins [1–4]. This process is catalyzed by NEDD8-activating enzyme (NAE, NAE1, and UBA3 heterodimer), transferred to NEDD8-conjugating enzymes E2 and Abbreviations: NEDD8, neural precursor cell expressed developmentally down-regulated 8; CRL, Cullin-RING E3 ligase; ESCC, Esophageal squamous cell carcinoma; CQ, chloroquine; BafA1, Bafilomycin A1; 3MA, 3-methyladenine; IB, immunoblotting; Com.C, Compound C. Accumulated studies show that protein neddylation is elevated in multiple human cancers, and inhibition of this pathway has been developed as a promising anticancer strategy. Neddylation inhibition induced pro-survival autophagic responses in cancer cells partially via modulating the HIF1–REDD1–TSC1 or DEPTOR–mTORC1 pathways [14–16]

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Conclusion