Ornithine decarboxylase as a therapeutic target for endometrial cancer

Abstract

Ornithine Decarboxylase (ODC) a key enzyme in polyamine biosynthesis is often overexpressed in cancers and contributes to polyamine-induced cell proliferation. We noted ubiquitous expression of ODC1 in our published endometrial cancer gene array data and confirmed this in the cancer genome atlas (TCGA) with highest expression in non-endometrioid, high grade, and copy number high cancers, which have the worst clinical outcomes. ODC1 expression was associated with worse overall survival and increased recurrence in three endometrial cancer gene expression datasets. Importantly, we confirmed these findings using quantitative real-time polymerase chain reaction (qRT-PCR) in a validation cohort of 60 endometrial cancers and found that endometrial cancers with elevated ODC1 had significantly shorter recurrence-free intervals (KM log-rank p = 0.0312, Wald test p = 5.59e-05). Difluoromethylornithine (DFMO) a specific inhibitor of ODC significantly reduced cell proliferation, cell viability, and colony formation in cell line models derived from undifferentiated, endometrioid, serous, carcinosarcoma (mixed mesodermal tumor; MMT) and clear cell endometrial cancers. DFMO also significantly reduced human endometrial cancer ACI-98 tumor burden in mice compared to controls (p = 0.0023). ODC-regulated polyamines (putrescine [Put] and/or spermidine [Spd]) known activators of cell proliferation were strongly decreased in response to DFMO, in both tumor tissue ([Put] (p = 0.0006), [Spd] (p<0.0001)) and blood plasma ([Put] (p<0.0001), [Spd] (p = 0.0049)) of treated mice. Our study indicates that some endometrial cancers appear particularly sensitive to DFMO and that the polyamine pathway in endometrial cancers in general and specifically those most likely to suffer adverse clinical outcomes could be targeted for effective treatment, chemoprevention or chemoprevention of recurrence.

Polyamine synthesis as a target of MYC oncogenes

“…We performed a number of preclinical studies over the years to investigate polyamine pathwayassociated enzymes and the impact of their inhibitors, including ODC/DFMO, SAMDC/SAM486A, DHPS/GC7, polyamine uptake receptor/AMXT-1501, SPR/sulfasalazine (8,10,11,(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25), and combinations thereof in neuroblastoma. More recently, we studied DFMO in osteosarcoma (135) and endometrial cancer (136). Notably, by early 2009, two excellent papers by the Hogarty and Cleveland groups had independently confirmed that DFMO inhibits tumor growth in vivo using the transgenic TH-MYCN neuroblastoma mouse model (131,137).…”

SKP2, positively regulated by circ_ODC1/miR‐422a axis, promotes the proliferation of retinoblastoma

“…20 For instance, Xu et al 21 Circ_ODC1 has never been probed before, but its host gene ODC1, a pivotal metabolic enzyme in polyamine synthesis, has already been validated as oncogenic in many cancers. 10,[27][28][29] In this current research, circ_ODC1 has been validated to sponge miR-422a and then deregulate SKP2. Moreover, SKP2 overexpression restored the suppression of RB proliferation in response to circ_ODC1 silence.…”

“…[10][11][12] Herein we assessed the expression of circ_ODC1 in RB and normal tissues. Through starBase2 (http://starbase.sysu.edu.cn/starbase2/index.php), we found circ_ODC1 to be the circular RNA (circRNA) that could bind to miR-422a.…”

“…Intriguingly, the host gene of circ_ODC1 has been reported as an oncogene in various cancers. [10][11][12] Herein we assessed the expression of circ_ODC1 in RB and normal tissues. The results of RT-qPCR indicated the upregulated expression of circ_ODC1 in RB tissues ( Figure 4A).…”

A plasma metabolite panel as biomarkers for early primary breast cancer detection

“…30 Polyamine putrescine is a product of ornithine, a reaction catalyzed by ornithine decarboxylase (ODC1), which is detectable in breast cancer cells and other cancer types. 31,32 Polyamines are essential for normal cell growth and development, and elevated levels have been associated with several different types of cancer. 33 The ornithine levels in primary breast cancer patients were lower than those in healthy controls, perhaps due to conversion to polyamine.…”