Pharmacological targeting of polyamine and hypusine biosynthesis reduces tumour activity of endometrial cancer

Endometrial cancer (EC) is a common and deadly cancer in women and novel therapeutic approaches are urgently needed. Polyamines (putrescine, spermidine, spermine) are critical for mammalian cell proliferation and MYC coordinately regulates polyamine metabolism through ornithine decarboxylase (ODC). ODC is a MYC target gene and rate-limiting enzyme of polyamine biosynthesis and the FDA-approved anti-protozoan drug α-difluoromethylornithine (DFMO) inhibits ODC activity and induces polyamine depletion that leads to tumour growth arrest. Spermidine is required for the hypusine-dependent activation of eukaryotic translation initiation factors 5A1 (eIF5A1) and 5A2 (eIF5A2) and connects the MYC/ODC-induced deregulation of spermidine to eIF5A1/2 protein translation, which is increased during cancer cell proliferation. We show that eIF5A1 is significantly upregulated in EC cells compared to control cells (<i>p</i>=.000038) and that combined pharmacological targeting of ODC and eIF5A hypusination with cytostatic drugs DFMO and N1-guanyl-1,7-diaminoheptane (GC7), respectively, reduces eIF5A1 activation and synergistically induces apoptosis in EC cells. <i>In vivo</i>, DFMO/GC7 suppressed xenografted EC tumour growth in mice more potently than each drug alone compared to control (<i>p</i>=.002) and decreased putrescine (<i>p</i>=.045) and spermidine levels in tumour tissues. Our data suggest DFMO and GC7 combination therapy may be useful in the treatment or prevention of EC.

子宫内膜癌（Endometrial Cancer, EC）是女性常见且致死性较高的恶性肿瘤，亟需新型治疗策略。多胺（腐胺、亚精胺、精胺）对哺乳动物细胞增殖至关重要，MYC可通过鸟氨酸脱羧酶（Ornithine Decarboxylase, ODC）协同调控多胺代谢通路。ODC是MYC的靶基因，同时也是多胺生物合成的限速酶；FDA批准的抗寄生虫药物α-二氟甲基鸟氨酸（α-difluoromethylornithine, DFMO）可抑制ODC活性，诱导多胺耗竭，进而阻滞肿瘤生长。亚精胺是真核翻译起始因子5A1（eukaryotic translation initiation factor 5A1, eIF5A1）与5A2（eIF5A2）发生羟腐胺赖氨酸依赖型激活的必需物质，其可将MYC/ODC介导的亚精胺代谢紊乱与癌症细胞增殖过程中增强的eIF5A1/2蛋白翻译过程相关联。本研究发现，相较于对照细胞，EC细胞内eIF5A1的表达水平显著上调（*p*=0.000038）；分别使用细胞生长抑制药物DFMO与N1-胍基-1,7-二氨基庚烷（N1-guanyl-1,7-diaminoheptane, GC7）靶向ODC与eIF5A的羟腐胺赖氨酸修饰，可降低eIF5A1的激活水平，并在EC细胞中协同诱导细胞凋亡。体内（*in vivo*）实验结果显示，相较于对照组，DFMO与GC7联合给药可更高效地抑制小鼠体内异种移植的EC肿瘤生长，其抗肿瘤效果优于单一药物给药组（*p*=0.002），同时可降低肿瘤组织内的腐胺水平（*p*=0.045）与亚精胺水平。本研究数据表明，DFMO与GC7联合疗法或可应用于子宫内膜癌的治疗与预防。