Centro de Investigaciones en Química Biológica de Córdoba, Universidad Nacional de Córdoba-The National Scientific and Technical Research Council, Departamento de Química Biológica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Ciudad Universitaria, Córdoba, Argentina.
PLoS One. 2013;8(1):e53211. doi: 10.1371/journal.pone.0053211. Epub 2013 Jan 2.
A shared characteristic of tumor cells is their exacerbated growth. Consequently, tumor cells demand high rates of phospholipid synthesis required for membrane biogenesis to support their growth. c-Fos, in addition to its AP-1 transcription factor activity, is the only protein known up to date that is capable of activating lipid synthesis in normal and brain tumor tissue. For this latter activity, c-Fos associates to the endoplasmic reticulum (ER) through its N-terminal domain and activates phospholipid synthesis, an event that requires it Basic Domain (BD) (aa 139-159). Fra-1, another member of the FOS family of proteins, is over-expressed in human breast cancer cells and its BD is highly homologous to that of c-Fos with two conservative substitutions in its basic amino acids. Consequently, herein we examined if Fra-1 and/or c-Fos participate in growth of breast cancer cells by activating phospholipid synthesis as found previously for c-Fos in brain tumors. We found both Fra-1 and c-Fos over-expressed in >95% of human ductal breast carcinoma biopsies examined contrasting with the very low or undetectable levels in normal tissue. Furthermore, both proteins associate to the ER and activate phospholipid synthesis in cultured MCF7 and MDA-MB231 breast cancer cells and in human breast cancer samples. Stripping tumor membranes of Fra-1 and c-Fos prior to assaying their lipid synthesis capacity in vitro results in non-activated lipid synthesis levels that are restored to their initial activated state by addition of Fra-1 and/or c-Fos to the assays. In MDA-MB231 cells primed to proliferate, blocking Fra-1 and c-Fos with neutralizing antibodies blocks lipid-synthesis activation and cells do not proliferate. Taken together, these results disclose the cytoplasmic activity of Fra-1 and c-Fos as potential targets for controlling growth of breast carcinomas by decreasing the rate of membrane biogenesis required for growth.
肿瘤细胞的一个共同特征是其过度生长。因此，肿瘤细胞需要高比率的磷脂合成来支持其生长，以满足膜生物发生的需要。c-Fos 除了其 AP-1 转录因子活性外，是迄今为止唯一已知能够激活正常和脑肿瘤组织中脂质合成的蛋白质。对于后一种活性，c-Fos 通过其 N 端结构域与内质网 (ER) 结合，并激活磷脂合成，这一事件需要其基本结构域 (BD)（aa139-159）。Fra-1 是 FOS 蛋白家族的另一个成员，在人类乳腺癌细胞中过度表达，其 BD 与 c-Fos 的高度同源，其碱性氨基酸中有两个保守取代。因此，在这里我们检查 Fra-1 和/或 c-Fos 是否通过激活磷脂合成来参与乳腺癌细胞的生长，就像以前在脑肿瘤中发现的 c-Fos 一样。我们发现 Fra-1 和 c-Fos 在 >95%的人乳腺导管癌活检中过度表达，而在正常组织中则非常低或检测不到。此外，这两种蛋白质都与 ER 结合，并在培养的 MCF7 和 MDA-MB231 乳腺癌细胞以及人乳腺癌样本中激活磷脂合成。在体外测定其脂质合成能力之前，从肿瘤膜中去除 Fra-1 和 c-Fos，导致非激活的脂质合成水平，通过向测定中添加 Fra-1 和/或 c-Fos，可将其恢复到初始激活状态。在 MDA-MB231 细胞中，用中和抗体阻断 Fra-1 和 c-Fos 的增殖，可阻断脂质合成的激活，细胞不会增殖。总之，这些结果揭示了 Fra-1 和 c-Fos 的细胞质活性可作为控制乳腺癌生长的潜在靶点，通过降低生长所需的膜生物发生速率。
