microRNAs与ABC转运蛋白介导的肿瘤多药耐药研究进展

目的回顾ABC转运蛋白与肿瘤耐药的研究现状,探讨miRNA在逆转肿瘤耐药过程中的作用机制。方法应用PubMed和CNKI期刊全文数据库检索系统,检索2010-01-01-2014-05-20的相关文献,以"ABC转运蛋白、miRNA和多药耐药"为关键词。纳入标准:1)ABC转运蛋白的表达水平与肿瘤耐药;2)miRNA对ABC转运蛋白表达水平的调控;3)miRNA对肿瘤细胞药物敏感性的影响,根据纳入标准符合分析的文献34篇。结果大多数癌症患者使用一种化疗药物治疗后,肿瘤细胞可能因为种种原因,不仅对该药产生耐药,而且对多种结构不同和作用机制完全不同的其他药物也产生交叉耐药。研究表明,在多药耐药导致肿瘤化疗失败的众多原因中,ABC转运蛋白过表达是导致肿瘤多药耐药的主要原因之一。在耐药肿瘤细胞当中高表达的ABC转运蛋白主要有乳腺癌耐药蛋白ABCG2,多药耐药相关蛋白ABCC1,P-糖蛋白ABCB1,这些蛋白采用ATP水解的能量将细胞内药物泵出细胞外,从而降低细胞内药物的浓度,使细胞产生耐药性。miRNA能与ABC转运蛋白mRNA的3′UTR结合,使mRNA降解或抑制其翻译,导致目标蛋白的表达受到抑制,从而增加肿瘤细胞的药物敏感性,逆转由ABC转运蛋白过表达引起的肿瘤多药耐药。结论 miRNA可以逆转由ABC转运蛋白家族高表达所引起的肿瘤耐药,这为肿瘤多药耐药的研究提供了新的思路。     

Targeting lactate transport suppresses in vivo breast tumour growth

Background

Most cancers, including breast cancer, have high rates of glucose consumption, associated with lactate production, a process referred as “Warburg effect”. Acidification of the tumour microenvironment by lactate extrusion, performed by lactate transporters (MCTs), is associated with higher cell proliferation, migration, invasion, angiogenesis and increased cell survival. Previously, we have described MCT1 up-regulation in breast carcinoma samples and demonstrated the importance of in vitro MCT inhibition. In this study, we performed siRNA knockdown of MCT1 and MCT4 in basal-like breast cancer cells in both normoxia and hypoxia conditions to validate the potential of lactate transport inhibition in breast cancer treatment.

Results

The effect of MCT knockdown was evaluated on lactate efflux, proliferation, cell biomass, migration and invasion and induction of tumour xenografts in nude mice. MCT knockdown led to a decrease in in vitro tumour cell aggressiveness, with decreased lactate transport, cell proliferation, migration and invasion and, importantly, to an inhibition of in vivo tumour formation and growth.

Conclusions

This work supports MCTs as promising targets in cancer therapy, demonstrates the contribution of MCTs to cancer cell aggressiveness and, more importantly, shows, for the first time, the disruption of in vivo breast tumour growth by targeting lactate transport.     

Nerve defect repair by differentiated adipose-derived stem cells and chondroitinase ABC-treated acellular nerves

Objective: To evaluate the effects of differentiated adipose-derived stem cells (dADSC) and chondroitinase ABC (ChABC)-treated acellular nerves (ACN) in building artificial nerves and repairing nerve defects. Methods: ADSC were isolated from the adipose tissue of Wistar rats, induced to differentiate into Schwann-like cells, and implanted into ChABC-treated ACN to repair a 15-mm sciatic nerve defect in Sprague–Dawley rats (the experimental group, group D). The control groups were an autologous nerve transplantation group (group E); ACN (group A), ChABC-treated ACN graft group (group B), and dADSC + ACN (group C). Twelve weeks after surgery, electromyography recordings, tricep surae muscle wet weight recovery rate, and axon counts were measured to evaluate the repair of peripheral nerve defects. Results: The nerve conduction velocity, compound muscle action potentials, tricep surae muscle wet weight recovery rate, and myelinated axon counts in the ChABC-ACN/dADSC group were significantly higher than in the other groups (P < 0.05), which were all lower than the autologous group (P < 0.05). Conclusions: The combination of ChABC-treated ACN and dADSC exhibited a synergistic effect in promoting nerve regeneration, and could be an alternative for effective tissue-engineered nerves.     

Multifaceted ABC transporters associated to microcin and bacteriocin export

Microcins and bacteriocins are ribosomally-synthesized defence peptides produced by Gram-negative and -positive bacteria to target competitors in their niche. Some of them carry posttranslational modifications established by dedicated enzymes. To protect themselves from their own toxic peptides, bacteria use dedicated immunity proteins or expel the toxin using ATP-binding cassette (ABC) transporters. In this last case, this immunity function is associated to export of the antimicrobial peptide out of the producing cells for targeting their competitors. Here we review the characteristics of these ABC-exporters and the mechanisms they use that unexpectedly cover from high promiscuity to high specificity or ensure another function concomitantly.     

Roles of FtsEX in cell division

FtsEX is a member of a small subclass of ABC transporters that uses mechano-transmission to perform work in the periplasm. FtsEX controls periplasmic peptidoglycan (PG) hydrolase activities in many Gram negative and positive organisms to ensure the safe separation of daughter cells during division. In these organisms FtsEX localizes to the Z ring and uses its ATPase activity to regulate its periplasmic effectors. In Escherichia coli, FtsEX also participates in building the divisome and coordinates PG synthesis with PG hydrolysis. This review discusses studies that are beginning to elucidate the mechanisms of FtsEX's various roles in cell division.     

The Lpt ABC transporter for lipopolysaccharide export to the cell surface

The surface of the outer membrane of Gram-negative bacteria is covered by a tightly packed layer of lipopolysaccharide molecules which provide a barrier against many toxic compounds and antibiotics. Lipopolysaccharide, synthesized in the cytoplasm, is assembled in the periplasmic leaflet of the inner membrane where the intermembrane Lpt system mediates its transport to the cell surface. The first step of lipopolysaccharide transport is its extraction from the outer leaflet of inner membrane powered by the atypical LptB₂FGC ABC transporter. Here we review latest advances leading to understanding at molecular level how lipopolysaccharide is transported irreversibly to the outer membrane.     

The amino acid transporter SLC6A14 in cancer and its potential use in chemotherapy

Tumor cells have an increased demand for glucose and amino acids to support their rapid growth, and also exhibit alterations in biochemical pathways that metabolize these nutrients. Transport across the plasma membrane is essential to feed glucose and amino acids into these tumor cell-selective metabolic pathways. Transfer of amino acids across biological membranes occurs via a multitude of transporters; tumor cells must upregulate one or more of these transporters to satisfy their increased demand for amino acids. Among the amino acid transporters, SLC6A14 stands out with specific functional features uniquely suited for the biological needs of the tumor cells. This transporter is indeed upregulated in tumors of epithelial origin, including colon cancer, cervical cancer, breast cancer, and pancreatic cancer. Since normal cells express this transporter only at low levels, blockade of this transporter should lead to amino acid starvation selectively in tumor cells, thus having little effect on normal cells. This offers a novel, yet logical, strategy for the treatment of cancers that are associated with upregulation of SLC6A14. In addition, a variety of amino acid-based prodrugs are recognized as substrates by SLC6A14, thus raising the possibility that anticancer drugs can be delivered into tumor cells selectively via this transporter in the form of amino acid prodrugs. This strategy allows exposure of SLC6A14-positive tumor cells to chemotherapy with minimal off-target effects. In conclusion, the amino acid transporter SLC6A14 holds great potential not only as a direct drug target for cancer therapy but also for tumor cell-selective delivery of anticancer drugs.