CNIH4 governs cervical cancer progression through reducing ferroptosis.

Cervical cancer is one of the most leading causes of cancer death worldwide, and ferroptosis is implicated in the progression of cervical cancer. Cornichon family AMPA receptor auxiliary protein 4 (CNIH4) is involved in the progression of various human cancers; however, its function in cervical cancer remains unclear. The present study aims to investigate the role and mechanism of CNIH4 in cervical cancer using gain- and loss-of-function studies in vitro. SiHa and CaSki cells were infected with lentiviral vectors to manipulate the expression of CNIH4 in vitro, and cell viability, migration, invasion as well as ferroptosis were evaluated. Transcriptome sequencing analysis was performed to further validate the mechanism through which CNIH4 regulated the progression of cervical cancer. The expression of CNIH4 was upregulated in human cervical cancer tissues and cells, and strongly correlated with the decreases in overall survival and disease free survival rates of cervical cancer patients. CNIH4 silence inhibited, while CNIH4 overexpression facilitated the survival of human cervical cancer cells. Mechanistically, CNIH4 elevated solute carrier family 7 member 11 (SLC7A11)-mediated cystine import, and subsequently increased intracellular glutathione synthesis and glutathione peroxidase 4 activity, thereby inhibiting ferroptosis of human cervical cancer cells. SLC7A11 silence significantly abolished CNIH4-mediated inhibition of ferroptosis in cervical cancer cells in vitro. Our study for the first time reveals that CNIH4 inhibits ferroptosis of human cervical cancer cells through upregulating SLC7A11, defining CNIH4 as an attractive therapeutic and prognostic target for cervical cancer.

Stapled peptide PROTAC induced significantly greater anti-PD-L1 effects than inhibitor in human cervical cancer cells.

Introduction: Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that target immune checkpoints that suppress immune cell activity. Low efficiency and high resistance are currently the main barriers to their clinical application. As a representative technology of targeted protein degradation, proteolysis-targeting chimeras (PROTACs) are considered to have potential for addressing these limitations. Methods: We synthesized a stapled peptide-based PROTAC (SP-PROTAC) that specifically targeted palmitoyltransferase ZDHHC3 and resulted in the decrease of PD-L1 in human cervical cancer cell lines. Flow cytometry, confocal microscopy, protein immunoblotting, Cellular Thermal Shift Assay (CETSA), and MTT assay analyses were conducted to evaluate the effects of the designed peptide and verify its safety in human cells. Results: In cervical cancer celllines C33A and HeLa, the stapled peptide strongly downregulated PD-L1 to < 50% of baseline level at 0.1 µM. DHHC3 expression decreased in both dosedependentand time-dependent manners. MG132, the proteasome inhibitor, can alleviate the SP-PROTAC mediated degradation of PD-L1 in human cancer cells. In a co-culture model of C33A and T cells, treatment with the peptide induced IFN-γ and TNF-α release in a dose-dependent manner by degrading PD-L1. These effects were more significant than that of the PD-L1 inhibitor, BMS-8. Conclusions: Cells treated with 0.1 µM of SP-PROTAC or BMS-8 for 4 h revealed that the stapled peptide decreased PD-L1 more effectively than BMS-8. DHHC3-targeting SP-PROTAC decreased PD-L1 in human cervical cancer more effectively than the inhibitor BMS-8.

A review of recent advances on single use of antibody-drug conjugates or combination with tumor immunology therapy for gynecologic cancer.

Immune checkpoint inhibitors have made significant progress in the treatment of various cancers. However, due to the low ICI responsive rate for the gynecologic cancer, ICI two-drug combination therapy tends to be a predominant way for clinical treatment. Antibody-drug conjugates, a promising therapeutic modality for cancer, have been approved by the FDA for breast cancer, lymphoma, multiple myeloma and gastric cancer. On September 2021, the FDA granted accelerated approval to tisotumab vedotin for patients with recurrent or metastatic cervical cancer. Currently, the role of therapy of ADCs on gynecologic tumors was also included in medication regimens. Now more than 30 ADCs targeting for 20 biomarkers are under clinical trials in the field, including monotherapy or combination with others for multiple lines of therapy. Some ADCs have been proved to enhance the antitumor immunity effect on both pre-clinical models and clinical trials. Therefore, combination of ADCs and ICIs are expected in clinical trials. In this review, we discuss current development of ADCs in gynecologic oncology and the combination effects of ICIs and ADCs.