α和β血红蛋白链的异二聚体作为一种固有的抗癌剂。
A heterodimer of α and β hemoglobin chains functions as an innate anticancer agent.
发表日期：2023 Sep 07
作者：
Maharrish Chelladurai, Dan Xu, Sivan Izraely, Shlomit Ben-Menachem, Roman Bengaiev, Orit Sagi-Assif, Weirong Yuan, Metsada Pasmanik Chor, Dave S Hoon, Wuyuan Lu, Isaac P Witz
来源：
BIOMEDICINE & PHARMACOTHERAPY
摘要：
转移 (以及肿瘤) 微环境中包含促癌和抑癌因子。这些相反力量之间的平衡决定了该转移至次要器官部位的癌细胞的命运。在寻找转移的微环境促进因子或抑制因子时，我们在之前的研究中确定了血红蛋白的β亚基(HBB)作为具有抗转移作用的肺源性因子。在本研究中，我们探索了调控黑色素瘤脑转移的机制，发现脑源性因子抑制了脑转移的黑色素瘤细胞的增殖，并诱导细胞凋亡和坏死。通过多种纯化方法，我们确定了由血红蛋白α链和β链组成的异二聚体具有这些抗转移功能。α或β亚基单独并不具有抑制作用。从人血红蛋白中化学纯化的α/β链二聚体抑制了原发黑色素瘤、黑色素瘤脑转移和乳腺癌细胞系的细胞存活率。二聚体引起了脑转移的四个黑色素瘤细胞系中的DNA损伤、细胞周期在SubG1阶段的停滞、细胞凋亡以及显著的细胞坏死。通过二聚体处理的黑色素瘤脑转移细胞的蛋白质组学分析表明，该二聚体下调了在癌细胞可持续性和进展中发挥关键作用的BRD4、GAB2和IRS2蛋白的表达。因此，我们假设血红蛋白二聚体作为一种抵抗脑转移癌细胞的抗性因子。© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.
Metastatic (as well as tumor) microenvironments contain both cancer-promoting and cancer-restraining factors. The balance between these opposing forces determines the fate of cancer cells that disseminate to secondary organ sites. In search for microenvironmental drivers or inhibitors of metastasis, we identified, in a previous study, the beta subunit of hemoglobin (HBB) as a lung-derived antimetastatic factor. In the present study, exploring mechanisms regulating melanoma brain metastasis, we discovered that brain-derived factors restrain proliferation and induce apoptosis and necrosis of brain-metastasizing melanoma cells. Employing various purification procedures, we identified a heterodimer composed of hemoglobin alpha and beta chains that perform these antimetastatic functions. Neither the alpha nor the beta subunit alone was inhibitory. An alpha/beta chain dimer chemically purified from human hemoglobin inhibited the cell viability of primary melanomas, melanoma brain metastasis (MBM), and breast cancer cell lines. The dimer-induced DNA damage, cell cycle arrest at the SubG1 phase, apoptosis, and significant necrosis in four MBM cell lines. Proteomic analysis of dimer-treated MBM cells revealed that the dimer downregulates the expression of BRD4, GAB2, and IRS2 proteins, playing crucial roles in cancer cell sustainability and progression. Thus, we hypothesize that the hemoglobin dimer functions as a resistance factor against brain-metastasizing cancer cells.© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.