Role of monocarboxylate transporter I/lactate dehydrogenase B-mediated lactate recycling in tamoxifen-resistant breast cancer cells

IF 6.9 3区 医学 Q1 CHEMISTRY, MEDICINAL
Min Chang Choi, Sang Kyum Kim, Young Jae Choi, Yong June Choi, Suntae Kim, Kyung Hwan Jegal, Sung Chul Lim, Keon Wook Kang
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引用次数: 0

Abstract

Although tamoxifen (TAM) is widely used in patients with estrogen receptor-positive breast cancer, the development of tamoxifen resistance is common. The previous finding suggests that the development of tamoxifen resistance is driven by epiregulin or hypoxia-inducible factor-1α-dependent glycolysis activation. Nonetheless, the mechanisms responsible for cancer cell survival and growth in a lactic acid-rich environment remain elusive. We found that the growth and survival of tamoxifen-resistant MCF-7 cells (TAMR-MCF-7) depend on glycolysis rather than oxidative phosphorylation. The levels of the glycolytic enzymes were higher in TAMR-MCF-7 cells than in parental MCF-7 cells, whereas the mitochondrial number and complex I level were decreased. Importantly, TAMR-MCF-7 cells were more resistant to low glucose and high lactate growth conditions. Isotope tracing analysis using 13C-lactate confirmed that lactate conversion to pyruvate was enhanced in TAMR-MCF-7 cells. We identified monocarboxylate transporter1 (MCT1) and lactate dehydrogenase B (LDHB) as important mediators of lactate influx and its conversion to pyruvate, respectively. Consistently, AR-C155858 (MCT1 inhibitor) inhibited the proliferation, migration, spheroid formation, and in vivo tumor growth of TAMR-MCF-7 cells. Our findings suggest that TAMR-MCF-7 cells depend on glycolysis and glutaminolysis for energy and support that targeting MCT1- and LDHB-dependent lactate recycling may be a promising strategy to treat patients with TAM-resistant breast cancer.

Abstract Image

Abstract Image

单羧酸转运体I/乳酸脱氢酶b介导的乳酸循环在他莫昔芬耐药乳腺癌细胞中的作用。
虽然他莫昔芬(TAM)被广泛用于雌激素受体阳性乳腺癌患者,但他莫昔芬耐药性的发展是常见的。先前的研究结果表明,他莫昔芬耐药的发生是由表调节蛋白或缺氧诱导因子-1α-依赖性糖酵解激活驱动的。尽管如此,癌细胞在富含乳酸的环境中存活和生长的机制仍然难以捉摸。我们发现耐他莫昔芬MCF-7细胞(TAMR-MCF-7)的生长和存活依赖于糖酵解而不是氧化磷酸化。与亲代MCF-7细胞相比,TAMR-MCF-7细胞中糖酵解酶水平较高,而线粒体数量和复合体I水平降低。重要的是,TAMR-MCF-7细胞对低葡萄糖和高乳酸的生长条件更有抵抗力。13c -乳酸同位素示踪分析证实,TAMR-MCF-7细胞中乳酸转化为丙酮酸的能力增强。我们发现单羧酸转运体1 (MCT1)和乳酸脱氢酶B (LDHB)分别是乳酸内流及其转化为丙酮酸的重要介质。同样,AR-C155858 (MCT1抑制剂)抑制TAMR-MCF-7细胞的增殖、迁移、球体形成和体内肿瘤生长。我们的研究结果表明TAMR-MCF-7细胞依赖糖酵解和谷氨酰胺解来获取能量,并支持靶向MCT1和ldhb依赖性乳酸再循环可能是治疗tam耐药乳腺癌患者的一种有希望的策略。
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来源期刊
CiteScore
13.40
自引率
9.00%
发文量
48
审稿时长
3.3 months
期刊介绍: Archives of Pharmacal Research is the official journal of the Pharmaceutical Society of Korea and has been published since 1976. Archives of Pharmacal Research is an interdisciplinary journal devoted to the publication of original scientific research papers and reviews in the fields of drug discovery, drug development, and drug actions with a view to providing fundamental and novel information on drugs and drug candidates.
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