Melittin inhibits proliferation, migration and invasion of bladder cancer cells by regulating key genes based on bioinformatics and experimental assays

Abstract

The antitumour effect of melittin (MEL) has recently attracted considerable attention. Nonetheless, information regarding the functional role of MEL in bladder cancer (BC) is currently limited. Herein, we investigated the effect of MEL on critical module genes identified in BC. In total, 2015 and 4679 differentially expressed genes (DEGs) associated with BC were identified from the GSE31189 set and The Cancer Genome Atlas database, respectively. GSE‐identified DEGs were mapped and analysed using Gene Ontology and Kyoto Encyclopaedia of Genes and Genomes analyses to determine BC‐involved crucial genes and signal pathways. Coupled with protein–protein interaction network and Molecular Complex Detection analyses, Modules 2 and 4 were highlighted in the progression of BC. In in‐vitro experiments, MEL inhibited the proliferation, migration, and invasion of UM‐UC‐3 and 5637 cells. The expression of NRAS, PAK2, EGFR and PAK1 in Module 4—enriched in the MAPK signalling pathway—was significantly reduced after treatment with MEL at concentrations of 4 or 6 μg/mL. Finally, quantitative reverse transcription‐polymerase chain reaction and Western blotting analyses revealed MEL inhibited the expression of genes at the mRNA (ERK1/2, ERK5, JNK and MEK5), protein (ERK5, MEK5, JNK and ERK1/2) and phosphorylation (p‐ERK1/2, p‐JNK, and p‐38) levels. This novel evidence indicates MEL exerts effects on the ERK5‐MAK pathway—a branch of MAPK signalling pathway. Collectively, these findings provide a theoretical basis for MEL application in BC treatment.

Cytotoxic and Pro-Apoptotic Effects of a Sub-Toxic Concentration of Fluvastatin on OVCAR3 Ovarian Cancer Cells After its Optimized Formulation to Melittin Nano-Conjugates

“…As clearly depicted, FLV-MEL nano-conjugates treatment strongly inhibited the proliferation of OVCAR3 cells, measured by the reduction of G1→S transition as well as the inhibition of the transition from G2 to M phase. These effects could depend on the ability of MEL to suppress the proliferation of cancer cells ( Tipgomut et al, 2018 ; Ceremuga et al, 2020 ; Yao et al, 2020 ) which acts synergistically with FLV ( Hillyard et al, 2002 ; Garwood et al, 2010 ; Hwang et al, 2017 ) even when used at a sub-toxic concentration.…”

Identification of hub genes in bladder cancer based on weighted gene co‐expression network analysis from TCGA database

“… 24 These findings could confirm our conclusions from another perspective. Meanwhile, according to previous studies, we found that TPM1 , 25 SYNM , 26 CSRP1 , 27 CFL2 , 28 HIP1R 29 are often found in the cancer genetic sequence of bladder cancer. 16 , 30 The protein encoded by TPM1 is a member of the widely distributed actin‐binding protein myosin (Tm) family, which participates in the contractile system of striated and smooth muscles and the cytoskeleton of non‐muscle cells, and studies have shown that TPM1 is a tumor suppressor gene 31 and plays a role in inhibiting the development of bladder urothelial carcinoma.…”

Downregulation of circ-RANBP9 in laryngeal cancer and its clinical significance

“…Four cascades exist in the MAPK signaling pathway: ERK1/2, p38 MAPK, c-Jun N-terminal kinase (JNK), and ERK5 (26). It has been shown that p38is involved in the invasion and metastasis of breast cancer ( 27), while ERK5 is involved in both cell proliferation in prostate cancer (28) and cell proliferation, migration, and invasion in bladder cancer (29). The focal adhesion signaling pathway has also been found to be related to the tumorigenesis and progression of various cancers (30).…”