Polyamine synthesis as a target of MYC oncogenes

Abstract

Edited by Ronald C. Wek This paper is in recognition of the 100th birthday of Dr. Herbert Tabor, a true pioneer in the polyamine field for over 70 years, who served as the editor-in-chief of the Journal of Biological Chemistry from 1971 to 2010. We review current knowledge of MYC proteins (c-MYC, MYCN, and MYCL) and focus on ornithine decarboxylase 1 (ODC1), an important bona fide gene target of MYC, which encodes the sentinel, rate-limiting enzyme in polyamine biosynthesis. Although notable advances have been made in designing inhibitors against the "undruggable" MYCs, their downstream targets and pathways are currently the main avenue for therapeutic anticancer interventions. To this end, the MYC-ODC axis presents an attractive target for managing cancers such as neuroblastoma, a pediatric malignancy in which MYCN gene amplification correlates with poor prognosis and high-risk disease. ODC and polyamine levels are often up-regulated and contribute to tumor hyperproliferation, especially of MYC-driven cancers. We therefore had proposed to repurpose ␣-difluoromethylornithine (DFMO), an FDA-approved, orally available ODC inhibitor, for management of neuroblastoma, and this intervention is now being pursued in several clinical trials. We discuss the regulation of ODC and polyamines, which besides their well-known interactions with DNA and tRNA/rRNA, are involved in regulating RNA transcription and translation, ribosome function, proteasomal degradation, the circadian clock, and immunity, events that are also controlled by MYC proteins.

Inhibition of the polyamine synthesis enzyme ornithine decarboxylase sensitizes triple-negative breast cancer cells to cytotoxic chemotherapy

“…An alternative mechanism that could account for ODC regulation is increased antizyme binding to ODC in response to chemotherapy. Moreover, since antizyme inhibitor (AZI) binds antizyme with a greater affinity than ODC, thereby protecting ODC from antizyme-mediated degradation (17,31), decreased AZI would free antizyme to bind ODC. Future studies are necessary to address which of these mechanisms is responsible for regulation of ODC in response to chemotherapy.…”

“…To investigate the mechanism by which ODC protein and activity are decreased following chemotherapy exposure, we first evaluated transcriptional regulation of ODC1, which is a well-characterized target of c-Myc (31). Depletion of c-Myc using siRNA did not alter the overall ODC response to chemotherapy ( Fig.…”

Inhibition of the polyamine synthesis enzyme ornithine decarboxylase sensitizes triple-negative breast cancer cells to cytotoxic chemotherapy

“…An alternative mechanism that could account for ODC regulation is increased antizyme binding to ODC in response to chemotherapy. Moreover, since antizyme inhibitor (AZI) binds antizyme with a greater affinity than ODC, thereby protecting ODC from antizyme-mediated degradation (15,24), decreased AZI would free antizyme to bind ODC. Future studies are necessary to address which of these mechanisms is responsible for regulation of ODC in response to chemotherapy.…”

“…DFMO is approved for treatment of trypanosomiasis and facial hirsutism, and is in clinical trials for treatment or prevention of various tumor types (22). DFMO is of particular chemotherapeutic interest in MYCN-amplified neuroblastoma, where Myc-driven overexpression of ODC contributes to tumor hyperproliferation (24). At the time of this study, the only studies of DFMO in combination with genotoxic chemotherapies are in brain tumors, and presently there are no clinical trials in breast cancer using DFMO as single agent therapy or in combination with other drugs.…”

“…To investigate the mechanism by which ODC protein and activity are decreased following chemotherapy exposure, we first evaluated transcriptional regulation of ODC1, which is a well-characterized target of c-Myc (24). Depletion of c-Myc using siRNA did not alter the overall ODC response to chemotherapy ( Fig.…”