Verapamil modulates NFAT2 to inhibit tumor growth and potentiates PD1ab immune checkpoint inhibitor therapy in cervical cancer treatment.

PURPOSE: Current evidence suggests a high co-prevalence of hypertension and cervical cancer. Accordingly, blood pressure control is indicated during anti-tumor drug therapy in this patient population. Over the past few years, immunotherapy has made great strides in treating different cancers. However, the role and clinical significance of verapamil as a first-line anti-hypertensive drug during immunotherapy remain poorly understood, emphasizing the need for further studies. METHODS: Murine cervical cancer models were employed to assess the effect of verapamil monotherapy and combination with PD1ab. Immunohistochemistry was conducted to quantify the abundance of CD8+ T cell and Ki67+ cells. Several in-vitro and in-vivo assays were used to study the effects of verapamil and explore the preliminary mechanism. RESULTS: Monotherapy with verapamil or PD1ab immune checkpoint inhibitor significantly suppressed the growth of subcutaneously grafted U14 cells in WT BABL/c mice, respectively, with increased survival time of mice. Consistent results were observed in the melanoma model. Furthermore, we substantiated that verapamil significantly impaired tumor proliferation and migration of SiHa human cervical cancer cells in vitro and in vivo. In silico analysis using TCGA data revealed that NFAT2 expression negatively correlated with patient survival. The CCK8 assay revealed that verapamil abrogated the stimulatory effect of NFAT2 after knockdown of NFAT2. CONCLUSIONS: Our results suggest that verapamil inhibits tumor growth by modulating NFAT2 expression and enhancing tumor immune responses to PD1ab, which can be harnessed for cervical cancer therapy, especially for patients with comorbid hypertension. Indeed, further clinical trials are warranted to increase the robustness of our findings.

Homologous genes shared between probiotics and pathogens affect the adhesion of probiotics and exclusion of pathogens in the gut mucus of shrimp.

Clarifying mechanisms underlying the selective adhesion of probiotics and competitive exclusion of pathogens in the intestine is a central theme for shrimp health. Under experimental manipulation of probiotic strain (i.e., Lactiplantibacillus plantarum HC-2) adhesion to the shrimp mucus, this study tested the core hypothesis that homologous genes shared between probiotic and pathogen would affect the adhesion of probiotics and exclusion of pathogens by regulating the membrane proteins of probiotics. Results indicated that the reduction of FtsH protease activity, which significantly correlated with the increase of membrane proteins, could increase the adhesion ability of L. plantarum HC-2 to the mucus. These membrane proteins mainly involved in transport (glycine betaine/carnitine/choline ABC transporter choS, ABC transporter, ATP synthase subunit a atpB, amino acid permease) and regulation of cellular processes (histidine kinase). The genes encoding the membrane proteins were significantly (p < 0.05) up-regulated except those encoding ABC transporters and histidine kinases in L. plantarum HC-2 when co-cultured with Vibrio parahaemolyticus E1, indicating that these genes could help L. plantarum HC-2 to competitively exclude pathogens. Moreover, an arsenal of genes predicted to be involved in carbohydrate metabolism and bacteria-host interactions were identified in L. plantarum HC-2, indicating a clear strain adaption to host's gastrointestinal tract. This study advances our mechanistic understanding of the selective adhesion of probiotics and competitive exclusion of pathogens in the intestine, and has important implications for screening and applying new probiotics for maintaining gut stability and host health.