Lee Ji-Eun, Seo Seung-Hwan, Ham Do-Won, Shin Eun-Hee
Department of Tropical Medicine and Parasitology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
Institute of Endemic Diseases, Medical Research Center, Seoul National University, Seoul 03080, Republic of Korea.
Biomol Ther (Seoul). 2025 Jul 1;33(4):621-635. doi: 10.4062/biomolther.2025.040. Epub 2025 Jun 25.
Despite its relatively low adenosine triphosphate (ATP) production efficiency, cancer cells reprogram their metabolism to utilize aerobic glycolysis for rapid proliferation. This "Warburg effect" not only provides biosynthetic precursors but also creates a tumor-favorable microenvironment. Key oncogenic regulators such as protein kinase B (AKT), nuclear factor kappa B (NF-κB), and cellular myelocytomatosis oncogene (c-Myc) enhance glycolytic activity by inducing the expression of enzymes including glucose transporters (GLUTs), hexokinase 2 (HK2), lactate dehydrogenase A (LDHA), and monocarboxylate transporters (MCTs). Moreover, telomerase reverse transcriptase (TERT), beyond its canonical role in telomere maintenance, also promotes glycolysis via the NF-κB and c-Myc pathways. From a therapeutic perspective, aerobic glycolysis contributes to glucose-mediated chemoresistance, limiting the efficacy of irinotecan in colorectal cancer (CRC). In this study, we investigated the role of -derived dense granule protein 16 (GRA16) in modulating glycolysis and irinotecan sensitivity. In HCT116 CRC cells stably expressing GRA16, AKT and NF-κB signaling were suppressed, leading to the downregulation of c-Myc and TERT. This resulted in decreased expression of GLUTs, HK2, LDHA, and MCTs, ultimately reducing glucose uptake and lactate production. Functional assays revealed that GRA16 induced G2/M cell cycle arrest, increased apoptosis, and suppressed proliferation. Notably, GRA16-expressing cells treated with irinotecan exhibited increased Sub-G1 accumulation and late-apoptotic and necrotic populations. Furthermore, siRNA-mediated silencing of c-Myc confirmed its key role in regulating TERT and glycolytic enzymes. These findings indicate that GRA16 suppresses aerobic glycolysis via the c-Myc/TERT axis and enhances irinotecan sensitivity, offering a promising strategy to overcome chemoresistance in CRC.
尽管癌细胞的三磷酸腺苷（ATP）产生效率相对较低，但它们会重新编程其代谢，以利用有氧糖酵解实现快速增殖。这种“瓦伯格效应”不仅提供生物合成前体，还创造了有利于肿瘤的微环境。关键的致癌调节因子，如蛋白激酶B（AKT）、核因子κB（NF-κB）和细胞髓细胞瘤致癌基因（c-Myc），通过诱导包括葡萄糖转运蛋白（GLUTs）、己糖激酶2（HK2）、乳酸脱氢酶A（LDHA）和单羧酸转运蛋白（MCTs）在内的酶的表达来增强糖酵解活性。此外，端粒酶逆转录酶（TERT）除了在维持端粒方面的经典作用外，还通过NF-κB和c-Myc途径促进糖酵解。从治疗角度来看，有氧糖酵解导致葡萄糖介导的化疗耐药性，限制了伊立替康在结直肠癌（CRC）中的疗效。在本研究中，我们研究了源自致密颗粒蛋白16（GRA16）在调节糖酵解和伊立替康敏感性中的作用。在稳定表达GRA16的HCT116 CRC细胞中，AKT和NF-κB信号被抑制，导致c-Myc和TERT下调。这导致GLUTs、HK2、LDHA和MCTs的表达降低，最终减少葡萄糖摄取和乳酸产生。功能分析表明，GRA16诱导G2/M细胞周期停滞，增加细胞凋亡，并抑制增殖。值得注意的是，用伊立替康处理的表达GRA16的细胞表现出Sub-G1积累增加以及晚期凋亡和坏死细胞群增加。此外，siRNA介导的c-Myc沉默证实了其在调节TERT和糖酵解酶中的关键作用。这些发现表明，GRA16通过c-Myc/TERT轴抑制有氧糖酵解并增强伊立替康敏感性，为克服CRC中的化疗耐药性提供了一种有前景的策略。
