GLUT5-KHK axis-mediated fructose metabolism drives proliferation and chemotherapy resistance of colorectal cancer.
GLUT5-KHK axis-mediated fructose metabolism drives proliferation and chemotherapy resistance of colorectal cancer.
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DOI：
10.1016/j.canlet.2022.215617
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发表时间：
2022-03
期刊：
影响因子：
9.7
通讯作者：
Z. Shen;Zhenkang Li;Yuecheng Liu;Yongsheng Li;Xiaochuang Feng;Yizhi Zhan;M. Lin;Chuanfa Fang-Chuanfa-Fan
中科院分区：
文献类型：
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作者：
Z. Shen;Zhenkang Li;Yuecheng Liu;Yongsheng Li;Xiaochuang Feng;Yizhi Zhan;M. Lin;Chuanfa Fang-Chuanfa-Fan
结直肠癌（CRC）是全世界癌症相关死亡的主要原因。丰富的代谢燃料被认为是CRC的潜在驱动因素。然而，目前还不清楚果糖，一种日常饮食中充足的糖，是否对CRC生长至关重要。在本研究中，我们发现人类CRC组织中的葡萄糖水平始终不足。为了弥补这一点，果糖被肿瘤细胞灵活地用作替代能源，以维持增殖并通过上调GLUT 5（SLC 2A 5编码的主要果糖转运蛋白）发挥体外化疗抗性。从机制上讲，在葡萄糖缺乏但富含果糖的环境中，GLUT 5可以与己酮糖激酶相互作用并抑制其自噬依赖性降解，从而将果糖捕获到糖酵解和三羧酸循环中，以促进CRC细胞的恶性生长。此外，减少饮食中果糖或药物阻断果糖的利用显著降低了CRC的生长，并使CRC细胞对体内化疗敏感。综上所述，我们的研究结果强调了由GLUT 5-KHK轴介导的果糖利用率升高在控制CRC生长中的作用，并暗示改善果糖摄入或抑制果糖介导的作用的努力可能作为潜在的治疗策略。
Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. Abundant metabolic fuels have been implicated as potential drivers of CRC. However, it remains unclear whether fructose, an ample sugar in daily diets, is essential for CRC growth. In the present study, we found that glucose levels were always insufficient in human CRC tissues. Compensating for this, fructose was flexibly utilized by tumor cells as an alternative energy source to maintain proliferation and exert chemotherapy resistancein vitroby upregulating GLUT5, a major fructose transporter encoded bySLC2A5. Mechanistically, in glucose-deprived but fructose-rich environments, GLUT5 could interact with ketohexokinase and inhibit its autophagy-dependent degradation, thus trapping fructose into glycolysis and tricarboxylic acid cycle for the malignant growth of CRC cells. In addition, reducing dietary fructose or pharmacological blockade of fructose utilization significantly reduced CRC growth and sensitized CRC cells to chemotherapyin vivo. Taken together, our findings highlight the role of elevated fructose utilization mediated by the GLUT5-KHK axis in governing CRC growth and imply that efforts to refine fructose intake or inhibit fructose-mediated actions may serve as potential therapeutic strategies.