SAICAR is an intermediate metabolite in the de novo synthesis pathway of purine nucleotides. SAICAR can selectively activate the pyruvate kinase M2 isoform (PKM2; EC50=0.3mM) in an isoform-specific manner[1-2]. The accumulation of SAICAR induces nuclear translocation of PKM2, phosphorylates and activates Erk1/2 signaling via PKM2, thereby promoting cell proliferation, including cancer cells[3-4].
In vitro, treatment of HeLa cells with SAICAR (0.5mM) for 30 minutes, SAICAR promotes phosphorylation of histone H3 and enhances c-Myc gene expression[5]. Under glucose deprivation conditions, exposure of HeLa, A549, U87, and H1299 cells to SAICAR (0–0.5mM) for 30 minutes. SAICAR promotes cancer cell survival under glucose-limited conditions while regulating glucose uptake and lactate production[6].
In vivo, SAICAR (100μM; 100μL) was topically injected into wounds of db/db diabetic mice once daily for 7 consecutive days. SAICAR significantly increased COL17 expression at the wound edge and the proportion of PCNA-positive proliferating epithelial cells, promoted wound re-epithelialization, accelerated wound closure, and improved delayed healing phenotypes[7].
References:
[1] Yan M, Chakravarthy S, Tokuda JM, et al. Succinyl-5-aminoimidazole-4-carboxamide-1-ribose 5'-Phosphate (SAICAR) Activates Pyruvate Kinase Isoform M2 (PKM2) in Its Dimeric Form. Biochemistry. 2016 Aug 23;55(33):4731-6.
[2] Ray SP, Duval N, Wilkinson TG 2nd, et al. Inherent properties of adenylosuccinate lyase could explain S-Ado/SAICAr ratio due to homozygous R426H and R303C mutations. Biochim Biophys Acta. 2013 Aug;1834(8):1545-53.
[3] Huo A, Xiong X. PAICS as a potential target for cancer therapy linking purine biosynthesis to cancer progression. Life Sci. 2023 Oct 15;331:122070.
[4] Yan M, Chakravarthy S, Tokuda JM, et al. Succinyl-5-aminoimidazole-4-carboxamide-1-ribose 5'-Phosphate (SAICAR) Activates Pyruvate Kinase Isoform M2 (PKM2) in Its Dimeric Form. Biochemistry. 2016 Aug 23;55(33):4731-6.
[5] Keller KE, Doctor ZM, Dwyer ZW, et al. SAICAR induces protein kinase activity of PKM2 that is necessary for sustained proliferative signaling of cancer cells. Mol Cell. 2014 Mar 6;53(5):700-9.
[6] Keller KE, Tan IS, Lee YS. SAICAR stimulates pyruvate kinase isoform M2 and promotes cancer cell survival in glucose-limited conditions. Science. 2012 Nov 23;338(6110):1069-72.
[7] Liu Y, Ho C, Wen D, et al. PKM2-mediated collagen XVII expression is critical for wound repair. JCI Insight. 2025 Jan 21;10(4):e184457.
SAICAR是嘌呤核苷酸从头合成途径中的一种中间代谢产物，SAICAR能够以同工酶选择性的方式激活丙酮酸激酶M2亚型（PKM2；EC50=0.3mM）[1-2]。SAICAR的积累可诱导PKM2发生核定位，并通过PKM2磷酸化并激活Erk1/2信号，诱导的细胞增殖，包括癌细胞[3-4]。
在体外，SAICAR（0.5mM）处理HeLa细胞30分钟，可促进细胞中组蛋白H3的磷酸化，并促进c-Myc基因表达[5]。SAICAR（0–0.5mM）在处理培养与葡萄糖剥夺条件的HeLa、A549、U87和H1299细胞30分钟，SAICAR进癌细胞在葡萄糖受限条件下的存活，同时调节葡萄糖摄取和乳酸生成[6]。
在体内，SAICAR（100μM；100μL）局部注射处理db/db糖尿病小鼠创面，每日一次，连续7天。SAICAR显著增加创缘COL17表达和上皮细胞增殖标志物PCNA阳性细胞比例，促进创面再上皮化进程，加速创面闭合速度，并改善延迟愈合表型[7]。