Novel c-Myc–Targeting Compound N, N-Bis (5-Ethyl-2-Hydroxybenzyl) Methylamine for Mediated c-Myc Ubiquitin-Proteasomal Degradation in Lung Cancer Cells

Abstract

Aberrant cellular Myc (c-Myc) is a common feature in the majority of human cancers and has been linked to oncogenic malignancies. Here, we developed a novel c-Myc-targeting compound, N, N-bis (5-ethyl-2-hydroxybenzyl) methylamine (EMD), and present evidence demonstrating its effectiveness in targeting c-Myc for degradation in human lung carcinoma. EMD exhibited strong cytotoxicity toward various human lung cancer cell lines, as well as chemotherapeutic-resistant patient-derived lung cancer cells, through apoptosis induction in comparison with chemotherapeutic drugs. The IC 50 of EMD against lung cancer cells was approximately 60 mM. Mechanistically, EMD eliminated c-Myc in the cells and initiated caspase-dependent apoptosis cascade. Cycloheximide chase assay revealed that EMD tended to shorten the half-life of c-Myc by approximately half. The cotreatment of EMD with the proteasome inhibitor MG132 reversed its c-Myc-targeting effect, suggesting the involvement of ubiquitinmediated proteasomal degradation in the process. We further verified that EMD strongly induced the ubiquitination of c-Myc and promoted protein degradation. c-Myc inhibition and apoptosis induction were additionally shown in hematologic malignant K562 cells, indicating the generality of the observed EMD effects. Altogether, we identified EMD as a novel potent compound targeting oncogenic c-Myc that may offer new opportunities for lung cancer treatment. SIGNIFICANCE STATEMENTThe deregulation of c-Myc is frequently associated with cancer progression. This study examined the effect of a new compound, N, N-bis (5-ethyl-2-hydroxybenzyl) methylamine (EMD), in targeting c-Myc in several lung cancer cell lines and drug-resistant primary lung cancer cells. EMD induced dramatic c-Myc degradation through a ubiquitin-proteasomal mechanism. The promising anticancer and c-Myc-targeted activities of EMD support its use in potential new approaches to treat c-Myc-driven cancer.

The role of ubiquitination and deubiquitination in cancer metabolism

“…Mutation or deletion of these E3 ligase genes induces carcinogenesis by attenuating c-Myc degradation. Anticancer drugs, including lanatoside C, diminish cancer cell growth by upregulating ubiquitination and degradation of c-Myc in cancer [ 161 – 163 ]. Ubiquitination of c-Myc can also be regulated by interaction with other molecules.…”

Aspiletrein A Induces Apoptosis Cell Death via Increasing Reactive Oxygen Species Generation and AMPK Activation in Non-Small-Cell Lung Cancer Cells

“…In addition, the apoptosis-inducing effect of AA and its molecular mechanism were confirmed in patient-derived lung cancer cells. The experiment in patient-derived cancer cells is widely accepted as an alternative approach in cancer research that minimizes animal use and provides precise molecular mechanisms mimicking humans and corresponding to the clinical response [ 52 , 53 , 54 , 55 ]. The in vitro 3D-tumorigenesis model provided an adequate cancer microenvironment, in which the cancer spheroid grown on matrix-like substance displays is ultimately functional of the cells and approximately relevant to the cancer microenvironment context [ 56 , 57 , 58 ].…”

Analysis of Protein–Protein Interactions Identifies NECTIN2 as a Target of N,N-Bis (5-Ethyl-2-hydroxybenzyl) Methylamine for Inhibition of Lung Cancer Metastasis

“…The novel c-MYC proto-oncogene bHLH transcription factor (MYC)-targeting compound N,N-bis (5-ethyl-2hydroxybenzyl) methylamine (EMD) is reported to have potential anticancer activity against various types of cancer cells (12). In our previous work, EMD was found to target and degrade the pro-oncogenic transcription factor c-MYC and initiate a caspase-dependent apoptosis cascade in lung cancer cells (13). In addition, EMD also demonstrated antimetastasis effects by inhibiting cell migration and suppressing filopodia formation in lung cancer cells (14).…”