A heterodimer of α and β hemoglobin chains functions as an innate anticancer agent

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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)561-572
Number of pages12
JournalInternational Journal of Cancer
Issue number3
StatePublished - 1 Feb 2024


FundersFunder number
Dr. Miriam and Sheldon G. Adelson Medical Research Foundation


    • brain metastasis
    • hemoglobin
    • innate anticancer immunity
    • melanoma
    • tumor microenvironment


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