乳腺癌中的谷氨酰胺代谢及潜在治疗靶点。
Glutamine metabolism in breast cancer and possible therapeutic targets.
作者信息
Li Shiqi, Zeng Hui, Fan Junli, Wang Fubing, Xu Chen, Li Yirong, Tu Jiancheng, Nephew Kenneth P, Long Xinghua
机构信息
Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China.
Center of Clinical Laboratory, Hangzhou Ninth People's Hospital, Hangzhou, China.
出版信息
Biochem Pharmacol. 2023 Apr;210:115464. doi: 10.1016/j.bcp.2023.115464. Epub 2023 Feb 26.
Cancer is characterized by metabolic reprogramming, which is a hot topic in tumor treatment research. Cancer cells alter metabolic pathways to promote their growth, and the common purpose of these altered metabolic pathways is to adapt the metabolic state to the uncontrolled proliferation of cancer cells. Most cancer cells in a state of nonhypoxia will increase the uptake of glucose and produce lactate, called the Warburg effect. Increased glucose consumption is used as a carbon source to support cell proliferation, including nucleotide, lipid and protein synthesis. In the Warburg effect, pyruvate dehydrogenase activity decreases, thereby disrupting the TCA cycle. In addition to glucose, glutamine is also an important nutrient for the growth and proliferation of cancer cells, an important carbon bank and nitrogen bank for the growth and proliferation of cancer cells, providing ribose, nonessential amino acids, citrate, and glycerin necessary for cancer cell growth and proliferation and compensating for the reduction in oxidative phosphorylation pathways in cancer cells caused by the Warburg effect. In human plasma, glutamine is the most abundant amino acid. Normal cells produce glutamine via glutamine synthase (GLS), but the glutamine synthesized by tumor cells is insufficient to meet their high growth needs, resulting in a "glutamine-dependent phenomenon." Most cancers have an increased glutamine demand, including breast cancer. Metabolic reprogramming not only enables tumor cells to maintain the reduction-oxidation (redox) balance and commit resources to biosynthesis but also establishes heterogeneous metabolic phenotypes of tumor cells that are distinct from those of nontumor cells. Thus, targeting the metabolic differences between tumor and nontumor cells may be a promising and novel anticancer strategy. Glutamine metabolic compartments have emerged as promising candidates, especially in TNBC and drug-resistant breast cancer. In this review, the latest discoveries of breast cancer and glutamine metabolism are discussed, novel treatment methods based on amino acid transporters and glutaminase are discussed, and the relationship between glutamine metabolism and breast cancer metastasis, drug resistance, tumor immunity and ferroptosis are explained, which provides new ideas for the clinical treatment of breast cancer.
癌症的特征是代谢重编程,这是肿瘤治疗研究中的一个热门话题。癌细胞改变代谢途径以促进其生长,这些改变的代谢途径的共同目的是使代谢状态适应癌细胞的无节制增殖。大多数处于非缺氧状态的癌细胞会增加葡萄糖摄取并产生乳酸,这被称为瓦伯格效应。增加的葡萄糖消耗被用作碳源来支持细胞增殖,包括核苷酸、脂质和蛋白质合成。在瓦伯格效应中,丙酮酸脱氢酶活性降低,从而扰乱三羧酸循环。除了葡萄糖,谷氨酰胺也是癌细胞生长和增殖的重要营养素,是癌细胞生长和增殖的重要碳库和氮库,为癌细胞生长和增殖提供核糖、非必需氨基酸、柠檬酸和甘油,并补偿瓦伯格效应导致的癌细胞氧化磷酸化途径的减少。在人体血浆中,谷氨酰胺是最丰富的氨基酸。正常细胞通过谷氨酰胺合成酶(GLS)产生谷氨酰胺,但肿瘤细胞合成的谷氨酰胺不足以满足其高生长需求,从而导致“谷氨酰胺依赖现象”。大多数癌症对谷氨酰胺的需求增加,包括乳腺癌。代谢重编程不仅使肿瘤细胞能够维持氧化还原平衡并将资源用于生物合成,还建立了与非肿瘤细胞不同的肿瘤细胞异质代谢表型。因此,针对肿瘤细胞和非肿瘤细胞之间的代谢差异可能是一种有前景的新型抗癌策略。谷氨酰胺代谢区室已成为有前景的候选者,尤其是在三阴性乳腺癌和耐药性乳腺癌中。在本综述中,讨论了乳腺癌和谷氨酰胺代谢的最新发现,讨论了基于氨基酸转运体和谷氨酰胺酶的新型治疗方法,并解释了谷氨酰胺代谢与乳腺癌转移、耐药性、肿瘤免疫和铁死亡之间的关系,这为乳腺癌的临床治疗提供了新思路。