Vorinostat upregulates MICA via the PI3K/Akt pathway to enhance the ability of natural killer cells to kill tumor cells.

Abstract

Vorinostat has good therapeutic efficacy against primary cutaneous T-cell lymphoma in the refractory stage. However, the molecular mechanism by which it inhibits solid tumors has not been clarified. To investigate the tumor inhibitory mechanism of vorinostat in cervical cancer, this study used Cell Counting Kit-8, flow cytometry, cell invasion and migration assays and the wound healing assay to evaluate the effects of vorinostat on cervical cancer cell proliferation, apoptosis, cell cycle, migration, and invasion. Real-time quantitative PCR and immunoblotting were used to detect gene and protein expression, respectively, of major histocompatibility class I-related chain A, phosphoinositide 3-kinase, phosphorylated PI3K p55 (Tyr199), and p-Akt (Ser473). The lactate dehydrogenase cytotoxicity assay was used to evaluate the ability of natural killer-92 cells to lyse cervical cancer cells. A xenograft nude mouse model was established to analyze the anti-tumor effect of vorinostat in vivo. Our results showed that vorinostat inhibited the proliferation, migration, and invasion of cervical cancer cells. Vorinostat also induced apoptosis and cell-cycle arrest in the S phase, inhibited PI3K (p110α), p-PI3K p55 (Tyr199), and p-Akt (Ser473) protein expression and upregulated MICA expression in vitro and in vivo, and promoted NK-92 cell-mediated cervical cancer cell lysis. The ability of vorinostat to upregulate MICA expression in cervical cancer cells was related to PI3K/Akt signaling. In brief, vorinostat upregulated MICA through the PI3K/Akt pathway and enhanced the sensitivity of cervical cancer cells to the NK cell-mediated cytolytic reaction. The results of this study demonstrate that vorinostat has anti-solid tumor effects on cervical cancer.

• Authors: Chenglai Xia, Zhihong He, Yantao Cai, Shaofen Liang
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 875 Pg. 173057 (May 15 2020) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 32135122 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier B.V. All rights reserved.

Chemical References

• Histocompatibility Antigens Class I
• Histone Deacetylase Inhibitors
• MHC class I-related chain A
• Vorinostat
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Apoptosis (drug effects)
• Cell Cycle Checkpoints (drug effects)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Histocompatibility Antigens Class I (metabolism)
• Histone Deacetylase Inhibitors (pharmacology, therapeutic use)
• Humans
• Killer Cells, Natural (drug effects, immunology)
• Mice
• Neoplasm Invasiveness (prevention & control)
• Phosphatidylinositol 3-Kinases (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Up-Regulation (drug effects)
• Uterine Cervical Neoplasms (drug therapy, pathology)
• Vorinostat (pharmacology, therapeutic use)
• Xenograft Model Antitumor Assays