Arsenic trioxide (ATO) induced degradation of Cyclin D1 sensitized PD-1/PD-L1 checkpoint inhibitor in oral and esophageal squamous cell carcinoma

Abstract

Arsenic trioxide (ATO) is widely studied for its antitumor efficacy and several recent studies suggested the immune modulatory effects of ATO in animal models. In this study we found ATO treatment induced increased ROS production and DNA damage in esophageal squamous cell carcinoma (ESCC) cells, led to DNA damage mediated degradation of Cyclin D1 and upregulation of PD-L1 in these cancer cells. Mechanistically, we found ATO induced a transient upregulation and nuclear translocation of Cyclin D1 by sumoylation. Followed with increased ubiquitination and degradation of Cyclin D1 through T286 phosphorylation, and at least partly mediated by Stat1 Y701 phosphorylation. We observed inversed correlations between Cyclin D1 and PD-L1 expression levels in human ESCC tissues. With 4NQO induced PD-L1 humanized mouse oral and esophageal squamous carcinoma model, we found combinatory administration of ATO and check point inhibitor resulted in a significant reduction of tumor volumes. Inversed correlation between Cyclin D1 with PD-L1 was also observed in the 4NQO induced mouse ESCC and OSCC model. Together, these data suggested ATO induced degradation of Cyclin D1 and functional suppression of CDK4/6 pathway sensitized OSCC and ESCC to checkpoint inhibitor treatment.

Brusatol From Brucea javanica Suppresses Arsenic Trioxide-Induced PD-L1 Upregulation Through Inhibition of NRF2 in Leukemia Cells

“…Specially ATO inhibited T-cell-mediated autoimmunity by inhibiting the proliferation of T lymphocytes, inducing CD4 + T-cell apoptosis and increasing the proportion of immunoinhibitory T reg cells, and its application may improve the clinical outcome of patients with severe aplastic anemia. 18,19 Additionally, Zhu et al 9 demonstrated that ATO induced the upregulation of PD-L1 in oral squamous carcinoma cells. Consistent with previous studies, we found that ATO significantly upregulated the expression of PD-L1 at both the protein and mRNA levels in NB4 and Jurkat cells.…”

“…Previous studies reported that ATO induced upregulation of PD-L1 in solid tumor cells. 9 To verify its effect on leukemia cells, ATO was used to treat NB4 and Jurkat cells for 24 h. As shown in Figure 1(A), ATO significantly enhanced the expression of PD-L1 at the protein level in NB4 and Jurkat cells compared with that in the control group cells. Due to glycosylation of the PD-L1 protein, 1-3 bands were apparent in the results.…”

“…8 A recent study showed that arsenic trioxide (ATO) induced upregulation of PD-L1 in oral squamous carcinoma cells, which significantly reduced its anticancer activity. 9 However, little is known about the role played by PD-L1 in leukemia. Previous studies have demonstrated that a proportion of acute promyelocytic leukemia (APL) patients are resistant to ATO therapy.…”

Metabolomics and transcriptomics joint analysis reveals altered amino acid metabolism in esophageal squamous cell carcinoma

“…The IHC staining procedure was processed as described previously (Zhu et al, 2020). In brie y, the tissue microarray slides were depara nized in xylene and gradient ethanol.…”

The Role of Oncogenes and Redox Signaling in the Regulation of PD-L1 in Cancer

“…Tumor cells frequently generate and secrete reactive oxygen species (ROS) and the resulting oxidative stress in the tumor microenvironment is now emerging as a potent PD-L1 inducer. Many studies have reported high PD-L1 expression associated with high generation of ROS but no direct link between these two observations has been investigated [200][201][202][203][204][205][206][207].…”