Glucose oxidation via the pentose phosphate pathway serves as the primary cellular mechanism for generating nicotinamide adenine dinucleotide phosphate (NADPH). The central regions of solid tumors typically experience glucose deficiency, emphasizing the need for sustained NADPH production crucial to tumor cell survival. This study highlights the crucial role of RIOK3 in maintaining NADPH production and colorectal cancer (CRC) cell survival during glucose deficiency. Our findings revealed upregulated RIOK3 expression upon glucose deprivation, with RIOK3 knockout significantly reducing cancer cell survival. Mechanistically, RIOK3 interacts with heat shock protein 90α (HSP90α), a chaperone integral to various cellular processes, thereby facilitating HSP90α binding to isocitrate dehydrogenase 1 (IDH1). This interaction further upregulates IDH1 expression, enhancing NADPH production and preserving redox balance. Furthermore, RIOK3 inhibition had no discernible effect on intracellular NADPH levels and cell death rates in HSP90α-knockdown cells. Collectively, our findings suggest that RIOK3 sustains colon cancer cell survival in low-glucose environments through an HSP90α-dependent pathway. This highlights the significance of the RIOK3–HSP90α–IDH1 cascade, providing insights into potential targeted therapeutic strategies for CRC in metabolic stress conditions.

通过戊糖磷酸途径的葡萄糖氧化是产生烟酰胺腺嘌呤二核苷酸磷酸 (NADPH) 的主要细胞机制。实体瘤的中心区域通常会出现葡萄糖缺乏，这强调了需要持续产生 NADPH，这对肿瘤细胞的存活至关重要。这项研究强调了 RIOK3 在葡萄糖缺乏期间维持 NADPH 产生和结直肠癌 (CRC) 细胞存活的关键作用。我们的研究结果显示，葡萄糖剥夺后 RIOK3 表达上调，敲除 RIOK3 显着降低癌细胞存活率。从机制上讲，RIOK3 与热休克蛋白 90α (HSP90α) 相互作用，热休克蛋白 90α 是各种细胞过程中不可或缺的分子伴侣，从而促进 HSP90α 与异柠檬酸脱氢酶 1 (IDH1) 结合。这种相互作用进一步上调 IDH1 表达，增强 NADPH 产生并保持氧化还原平衡。此外，RIOK3 抑制对 HSP90α 敲低细胞中的细胞内 NADPH 水平和细胞死亡率没有明显影响。总的来说，我们的研究结果表明，RIOK3 通过 HSP90α 依赖性途径维持结肠癌细胞在低葡萄糖环境中的存活。这凸显了 RIOK3-HSP90α-IDH1 级联的重要性，为代谢应激条件下 CRC 的潜在靶向治疗策略提供了见解。