de la Ballina Laura R, Cano-Crespo Sara, González-Muñoz Elena, Bial Susanna, Estrach Soline, Cailleteau Laurence, Tissot Floriane, Daniel Hannelore, Zorzano Antonio, Ginsberg Mark H, Palacín Manuel, Féral Chloé C
From the Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028 Barcelona, Spain and Department of Biochemistry and Molecular Biology, University of Barcelona, 08028 Barcelona, Spain, INSERM, U1081, Institute for Research on Cancer and Aging, Nice (IRCAN), University of Nice Sophia-Antipolis, CNRS UMR 7284, 06107 Nice, France,
From the Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028 Barcelona, Spain and Department of Biochemistry and Molecular Biology, University of Barcelona, 08028 Barcelona, Spain, Spanish Biomedical Research Network in Rare Diseases (CIBERER U-731), 08028 Barcelona, Spain.
J Biol Chem. 2016 Apr 29;291(18):9700-11. doi: 10.1074/jbc.M115.704254. Epub 2016 Mar 5.
CD98hc functions as an amino acid (AA) transporter (together with another subunit) and integrin signaling enhancer. It is overexpressed in highly proliferative cells in both physiological and pathological conditions. CD98hc deletion induces strong impairment of cell proliferation in vivo and in vitro Here, we investigate CD98hc-associated AA transport in cell survival and proliferation. By using chimeric versions of CD98hc, the two functions of the protein can be uncoupled. Although recovering the CD98hc AA transport capacity restores the in vivo and in vitro proliferation of CD98hc-null cells, reconstitution of the integrin signaling function of CD98hc is unable to restore in vitro proliferation of those cells. CD98hc-associated transporters (i.e. xCT, LAT1, and y(+)LAT2 in wild-type cells) are crucial to control reactive oxygen species and intracellular AA levels, thus sustaining cell survival and proliferation. Moreover, in CD98hc-null cells the deficiency of CD98hc/xCT cannot be compensated, leading to cell death by ferroptosis. Supplementation of culture media with β-mercaptoethanol rescues CD98hc-deficient cell survival. Under such conditions null cells show oxidative stress and intracellular AA imbalance and, consequently, limited proliferation. CD98hc-null cells also present reduced intracellular levels of branched-chain and aromatic amino acids (BCAAs and ARO AAs, respectively) and induced expression of peptide transporter 1 (PEPT1). Interestingly, external supply of dipeptides containing BCAAs and ARO AAs rescues cell proliferation and compensates for impaired uptake of CD98hc/LAT1 and CD98hc/y(+)LAT2. Our data establish CD98hc as a master protective gene at the cross-road of redox control and AA availability, making it a relevant therapeutic target in cancer.
CD98重链作为一种氨基酸（AA）转运体（与另一个亚基共同作用）和整合素信号增强子发挥作用。在生理和病理条件下，它在高增殖细胞中均有过表达。CD98重链缺失在体内和体外均会强烈损害细胞增殖。在此，我们研究与CD98重链相关的AA转运在细胞存活和增殖中的作用。通过使用CD98重链的嵌合变体，该蛋白的两种功能可以解偶联。尽管恢复CD98重链的AA转运能力可恢复CD98重链缺失细胞的体内和体外增殖，但重建CD98重链的整合素信号功能却无法恢复这些细胞的体外增殖。与CD98重链相关的转运体（即野生型细胞中的xCT、LAT1和y(+)LAT2）对于控制活性氧和细胞内AA水平至关重要，从而维持细胞存活和增殖。此外，在CD98重链缺失的细胞中，CD98重链/xCT的缺陷无法得到补偿，导致细胞因铁死亡而死亡。用β-巯基乙醇补充培养基可挽救CD98重链缺陷细胞的存活。在这种条件下，缺失细胞表现出氧化应激和细胞内AA失衡，因此增殖受限。CD98重链缺失的细胞还呈现出细胞内支链和芳香族氨基酸（分别为BCAAs和ARO AAs）水平降低以及肽转运体1（PEPT1）表达上调。有趣的是，外部供应含BCAAs和ARO AAs的二肽可挽救细胞增殖并补偿CD98重链/LAT1和CD98重链/y(+)LAT2摄取受损的情况。我们的数据确立了CD98重链作为氧化还原控制和AA可用性交叉点上的主要保护基因，使其成为癌症治疗的相关靶点。
