谷氨酰胺转运体 SNAT2/SLC38A2 的表达增加促进了谷氨酰胺依赖性和氧化应激抗性，并与三阴性乳腺癌的预后不良相关。

Increased expression of glutamine transporter SNAT2/SLC38A2 promotes glutamine dependence and oxidative stress resistance, and is associated with worse prognosis in triple-negative breast cancer.

机构信息

Hypoxia and Angiogenesis Group, Weatherall Institute of Molecular Medicine, Department of Oncology, University of Oxford, Oxford, OX3 9DS, UK.

Nottingham Breast Cancer Research Centre, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham Biodiscovery Institute, Nottingham, NG7 2RD, UK.

出版信息

Br J Cancer. 2021 Jan;124(2):494-505. doi: 10.1038/s41416-020-01113-y. Epub 2020 Oct 8.

BACKGROUND

Glutamine (Gln) is an abundant nutrient used by cancer cells. Breast cancers cells and particularly triple-receptor negative breast cancer (TNBC) are reported to be dependent on Gln to produce the energy required for survival and proliferation. Despite intense research on the role of the intracellular Gln pathway, few reports have focussed on Gln transporters in breast cancer and TNBC.

METHODS

The role and localisation of the Gln transporter SLC38A2/SNAT2 in response to Gln deprivation or pharmacological stresses was examined in a panel of breast cancer cell lines. Subsequently, the effect of SLC38A2 knockdown in Gln-sensitive cell lines was analysed. The prognostic value of SLC38A2 in a cohort of breast cancer was determined by immunohistochemistry.

RESULTS

SLC38A2 was identified as a strongly expressed amino acid transporter in six breast cancer cell lines. We confirmed an autophagic route of degradation for SLC38A2. SLC38A2 knockdown decreased Gln consumption, inhibited cell growth, induced autophagy and led to ROS production in a subgroup of Gln-sensitive cell lines. High expression of SLC38A2 protein was associated with poor breast cancer specific survival in a large cohort of patients (p = 0.004), particularly in TNBC (p = 0.02).

CONCLUSIONS

These results position SLC38A2 as a selective target for inhibiting growth of Gln-dependent breast cancer cell lines.

背景

谷氨酰胺（Gln）是一种丰富的营养物质，被癌细胞所利用。有报道称，乳腺癌细胞，尤其是三阴性乳腺癌（TNBC），依赖 Gln 来产生生存和增殖所需的能量。尽管对细胞内 Gln 途径的作用进行了深入研究，但很少有报道关注乳腺癌和 TNBC 中的 Gln 转运体。

方法

在一系列乳腺癌细胞系中，研究了 Gln 转运体 SLC38A2/SNAT2 对 Gln 剥夺或药物应激的作用及其定位。随后，分析了 SLC38A2 敲低对 Gln 敏感细胞系的影响。通过免疫组织化学法确定了 SLC38A2 在乳腺癌队列中的预后价值。

结果

SLC38A2 被鉴定为六种乳腺癌细胞系中表达强烈的氨基酸转运体。我们证实了 SLC38A2 的自噬降解途径。SLC38A2 敲低降低了 Gln 消耗，抑制了细胞生长，诱导了自噬，并导致 Gln 敏感细胞系中 ROS 的产生。在一大组患者中，SLC38A2 蛋白的高表达与乳腺癌特异性生存不良相关（p=0.004），尤其是在 TNBC 中（p=0.02）。