Identification of the anticancer effects of a novel proteasome inhibitor, ixazomib, on colorectal cancer using a combined method of microarray and bioinformatics analysis

Abstract

PurposeThe study aimed to explore the anticancer effects of a novel proteasome inhibitor, ixazomib, on colorectal cancer (CRC) using a combined method of microarray and bioinformatics analysis.Materials and methodsCell proliferation was tested by Cell Counting Kit-8 (CCK-8) assay for SW620 cells treated with different concentrations of ixazomib and different treatment times. The microarray analysis was conducted for six samples, including three samples of SW620 cells untreated with ixazomib and three samples of SW620 cells treated with ixazomib. The differentially expressed genes (DEGs) between untreated and treated samples were identified by the Linear Models for Microarray data (LIMMA) package in R language. The Gene Ontology (GO) functional and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed for the DEGs using the Database for Annotation, Visualization and Integrated Discovery (DAVID) and KEGG Orthology-Based Annotation System (KOBAS) online tool. The protein–protein interaction (PPI) network was constructed using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database, and module analysis was performed for the PPI network.ResultsIxazomib could inhibit the proliferation of SW620 cells in a dose-dependent and time-dependent manner. A total of 743 DEGs, including 203 upregulated DEGs such as HSPA6 and 540 downregulated DEGs such as APCDD1, were identified. Eighty-three GO terms were enriched for DEGs, which were mainly related to protein folding, apoptotic process, transcription factor activity, and proteasome. Thirty-seven KEGG pathways were perturbed, including pathway of apoptosis and cell cycle. Forty-six hub genes, such as TP53, JUN, and ITGA2, were screened out, and three modules with important functions were mined from the PPI network.ConclusionThe novel proteasome inhibitor ixazomib significantly inhibited the proliferation of human CRC SW620 cells. It exerted anticancer effects through targeting the expression of DEGs, such as HSPA6, APCDD1, TP53, and JUN, and affecting the signaling pathways including apoptosis and cell cycle pathway, which demonstrated the promising potential of ixazomib for CRC therapy.

Proteomic and bioinformatic analysis of condyloma acuminata: mild hyperthermia treatment reveals compromised HPV infectivity of keratinocytes via regulation of metabolism, differentiation and anti-viral responses

“…Therefore, we proposed that by induction of these key factors, hyperthermia has the potential to interfere with HPV DNA replication and expression as well as HPV antigen presentation and, in this way, boost the immunologic clearance of HPV infections. Usually, proteins within the same interaction module possess similar functions [37], and the GO-BP enrichment analysis of the two major interaction modules mined from the PPI-network revealed a highly similar functional involvement as compared to those identified by clustering, indicating that the interaction modules mined from the PPI network were crucial to the overall proteomic changes that result from hyperthermia, and therefore worthed further attention and more detailed investigations.…”

“…The grayscale analysis of western blot results was shown in barplot (L). CA samples were assigned to either 37 C control group (37) or 44 C hyperthermia (44). Asterisk ( Ã ) indicates statistically significant differences between the hyperthermia and control groups, whereas ns indicates non-significant differences.…”

BaxΔ2 sensitizes colorectal cancer cells to proteasome inhibitor-induced cell death

“…These inhibitors can cause apoptosis, mainly through protein accumulation-mediated cellular stress or proteotoxicity [ 1 , 3 , 4 ]. Several proteasome inhibitors have been approved by the FDA or are undergoing clinical and pre-clinical studies for cancer therapy [ 5 – 10 ]. The primary applications of proteasome inhibitors in cancer therapy are for the treatment of multiple myeloma or mantle cell lymphoma [ 2 , 3 , 11 , 12 ].…”

“…While bortezomib is only approved to treat of multiple myeloma and mantle cell lymphoma, multiple studies have shown that the use of bortezomib in concert with other chemotherapeutics can significantly increase cell death in solid tumors [ 8 – 10 , 15 , 16 ]. Ixazomib is another reversible boronate proteasome inhibitor, which recently gained clinical approval for treatment of multiple myeloma, and has also shown the ability to inhibit proliferation and induce apoptosis in solid tumors [ 2 , 3 , 5 , 12 ]. On the other hand, carfilzomib, is a potent irreversible proteasome inhibitor approved for treatment of multiple myeloma, especially in patients who didn’t respond well to previous treatment with bortezomib [ 2 , 3 , 7 , 12 ].…”

Ixazomib promotes CHOP-dependent DR5 induction and apoptosis in colorectal cancer cells

“…10 Previously studies reported that ixazomib induces apoptosis in a verity of cancers including liver cance, 11 melanom 12 and CR. 13,14 The above unique features of ixazomib may help to maintain optimal serum concentrations of ixazomib and improve treatment convenience for the patient.…”