Post-Transcriptional Regulation of Rab7a in Lysosomal Positioning and Drug Resistance in Nutrient-Limited Cancer Cells.

IF 3.6 3区生物学 Q3 CELL BIOLOGY Traffic Pub Date : 2024-09-01 DOI:10.1111/tra.12956

Aliye Ezgi Güleç Taşkıran, Hepşen H Hüsnügil, Zahra E Soltani, Göksu Oral, Nazlı S Menemenli, Chuanpit Hampel, Kerstin Huebner, Katharina Erlenbach-Wuensch, Ilir Sheraj, Regine Schneider-Stock, Aytekin Akyol, Nalan Liv, Sreeparna Banerjee

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Abstract

Limited nutrient availability in the tumor microenvironment can cause the rewiring of signaling and metabolic networks to confer cancer cells with survival advantages. We show here that the limitation of glucose, glutamine and serum from the culture medium resulted in the survival of a population of cancer cells with high viability and capacity to form tumors in vivo. These cells also displayed a remarkable increase in the abundance and size of lysosomes. Moreover, lysosomes were located mainly in the perinuclear region in nutrient-limited cells; this translocation was mediated by a rapid post-transcriptional increase in the key endolysosomal trafficking protein Rab7a. The acidic lysosomes in nutrient-limited cells could trap weakly basic drugs such as doxorubicin, mediating resistance of the cells to the drug, which could be partially reversed with the lysosomal inhibitor bafilomycin A1. An in vivo chorioallantoic membrane (CAM) assay indicated a remarkable decrease in microtumor volume when nutrient-limited cells were treated with 5-Fluorouracil (5-FU) and bafilomycin A1 compared to cells treated with either agent alone. Overall, our data indicate the activation of complementary pathways with nutrient limitation that can enable cancer cells to survive, proliferate and acquire drug resistance.

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转录后调控 Rab7a 在营养有限的癌细胞溶酶体定位和抗药性中的作用

肿瘤微环境中有限的营养供应可导致信号和代谢网络的重新布线，从而赋予癌细胞生存优势。我们在此表明，限制培养基中的葡萄糖、谷氨酰胺和血清会导致一批具有高存活率和在体内形成肿瘤能力的癌细胞存活下来。这些细胞的溶酶体数量和大小也显著增加。此外，在营养受限的细胞中，溶酶体主要位于核周区域；这种转移是由关键的溶酶体内转运蛋白 Rab7a 的转录后快速增加所介导的。营养受限细胞中的酸性溶酶体能捕获多柔比星等弱碱性药物，从而导致细胞对药物产生抗药性，而溶酶体抑制剂巴佛洛霉素 A1 能部分逆转这种抗药性。体内绒毛膜（CAM）试验表明，与单独使用其中一种药物处理细胞相比，使用5-氟尿嘧啶（5-FU）和巴非罗霉素A1处理营养受限细胞时，微瘤体积显著减少。总之，我们的数据表明，营养限制激活了互补途径，可使癌细胞存活、增殖并获得抗药性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Traffic 生物-细胞生物学

CiteScore

8.10

自引率

2.20%

发文量

审稿时长

2 months

期刊介绍： Traffic encourages and facilitates the publication of papers in any field relating to intracellular transport in health and disease. Traffic papers span disciplines such as developmental biology, neuroscience, innate and adaptive immunity, epithelial cell biology, intracellular pathogens and host-pathogen interactions, among others using any eukaryotic model system. Areas of particular interest include protein, nucleic acid and lipid traffic, molecular motors, intracellular pathogens, intracellular proteolysis, nuclear import and export, cytokinesis and the cell cycle, the interface between signaling and trafficking or localization, protein translocation, the cell biology of adaptive an innate immunity, organelle biogenesis, metabolism, cell polarity and organization, and organelle movement. All aspects of the structural, molecular biology, biochemistry, genetics, morphology, intracellular signaling and relationship to hereditary or infectious diseases will be covered. Manuscripts must provide a clear conceptual or mechanistic advance. The editors will reject papers that require major changes, including addition of significant experimental data or other significant revision. Traffic will consider manuscripts of any length, but encourages authors to limit their papers to 16 typeset pages or less.