Network Analysis Identifies Drug Targets and Small Molecules to Modulate Apoptosis Resistant Cancers

Abstract

Programed cell death or apoptosis fails to induce cell death in many recalcitrant cancers. Thus, there is an emerging need to activate the alternate cell death pathways in such cancers. In this study, we analyzed the apoptosis-resistant colon adenocarcinoma, glioblastoma multiforme, and small cell lung cancers transcriptome profiles. We extracted clusters of non-apoptotic cell death genes from each cancer to understand functional networks affected by these genes and their role in the induction of cell death when apoptosis fails. We identified transcription factors regulating cell death genes and protein–protein interaction networks to understand their role in regulating cell death mechanisms. Topological analysis of networks yielded FANCD2 (ferroptosis, negative regulator, down), NCOA4 (ferroptosis, up), IKBKB (alkaliptosis, down), and RHOA (entotic cell death, down) as potential drug targets in colon adenocarcinoma, glioblastoma multiforme, small cell lung cancer phenotypes respectively. We also assessed the miRNA association with the drug targets. We identified tumor growth-related interacting partners based on the pathway information of drug-target interaction networks. The protein–protein interaction binding site between the drug targets and their interacting proteins provided an opportunity to identify small molecules that can modulate the activity of functional cell death interactions in each cancer. Overall, our systematic screening of non-apoptotic cell death-related genes uncovered targets helpful for cancer therapy.

Molecular identification of an immunity- and Ferroptosis-related gene signature in non-small cell lung Cancer

“…The risk model proposed in this study was composed of five ferroptosis-related genes: FANCD2 , GCLC , SLC7A11 , ALOX15 , and DPP4 . FANCD2 is a nuclear protein involved in DNA damage repair and has been reported to protect against ferroptosis-mediated injury in cases of colon adenocarcinoma, clear cell renal cell carcinoma, and low-grade glioma [ 24 – 26 ]. Glutamate cysteine ligase is composed of the catalytic subunit GCLC , which evidently has a glutathione-independent, non-canonical role in conferring protection against ferroptosis, and this is achieved via the maintenance of glutamate homeostasis under cystine starvation [ 27 – 29 ].…”

Molecular Identification of Immunity- and Ferroptosis-related Gene Signature in Non-small Cell Lung Cancer

“…The prognostic model proposed in this study was composed of 5 ferroptosis-related genes (FANCD2, GCLC, SLC7A11, ALOX15 and DPP4). FANCD2 is a nuclear protein involved in DNA damage repair, which medicates ferroptosis in colon adenocarcinoma, clear cell renal cell carcinoma and glioma (21)(22)(23). GCLC, a glutamate-cysteine ligase catalytic subunit, acts as a glutathione-independent, non-canonical role in the protection against ferroptosis by maintaining glutamate homeostasis under cystine starvation (24)(25)(26).…”

In silico Methods for Identification of Potential Therapeutic Targets

“…Finally, a network centrality analysis identified four hub genes (CTGF, HCK, LYN, PDGFRB) as potential therapeutic targets [125]. In another example, Fathima et al used non-apoptotic cell death genes of colon adenocarcinoma (COAD), glioblastoma multiforme (GBM), and small cell lung cancer (SCLC) screened from their transcriptome profiles to build three PPI networks [133]. Through centrality analysis, 4 of the top 10 hub proteins, which were not found or only found in one target database, were considered as novel valid therapeutic targets (FANCD2 and NCOA4 for COAD, IKBKB for GBM, and RHOA for GBM and SCLC) [133].…”