Heme Sequestration as an Effective Strategy for the Suppression of Tumor Growth




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Heme is an essential prosthetic group in proteins and enzymes involved in oxygen utilization and metabolism. Heme also plays versatile and fascinating roles in regulating fundamental biological processes ranging from aerobic respiration to drug metabolism. Increasing experimental and epidemiological data have also shown that altered heme homeostasis accelerates the development and progression of common diseases, including various cancers, diabetes, vascular diseases, and Alzheimer's disease. The effects of heme on the pathogenesis of these diseases may be mediated via its action on various cellular signaling and regulatory proteins, as well as its function in cellular bioenergetics, specifically, oxidative phosphorylation (OXPHOS). Elevated heme levels in cancer cells intensify OXPHOS, leading to higher ATP generation and fueling tumorigenic functions. In contrast, lowered heme levels in neurons may reduce OXPHOS, leading to defects in bioenergetics and causing neurological deficits. Additionally, heme has been shown to modulate the activities of diverse cellular proteins influencing disease pathogenesis. These include tumor suppressor P53 protein, progesterone receptor membrane component 1 protein PGRMC1, cystathionine-βsynthase CBS, and the nuclear receptor subfamily member Rev-Erbα. Here, we generated small heme-sequestering proteins (HeSPs) based on bacterial hemophores. These HeSPs contain neutral mutations in the heme-binding pocket of hemophores and hybrid sequences from hemophores of different bacteria. We showed that HeSPs bound to heme and effectively extracted heme from hemoglobin. They strongly inhibited heme uptake and cell proliferation and induced apoptosis in non-small lung cancer (NSCLC) cells, while their effects on non-tumorigenic cell lines representing normal lung cells were not significant. HeSPs strongly suppressed the growth of human NSCLC tumor xenografts in mice. HeSPs decreased oxygen consumption rates and ATP levels in tumor cells isolated from treated mice, while they did not affect liver and blood cell functions. Immunohistochemistry revealed that HeSPs reduced the levels of key enzymes and transporters involved in heme synthesis and uptake, as well as the uptake and metabolism of the main fuels for cancer cells, glucose and glutamine. Further, we found that HeSPs reduced the levels of angiogenic and vascular markers, as well as vessel density in tumor tissues. Together, these results demonstrate that HeSPs act via multiple mechanisms, including the inhibition of oxidative phosphorylation, to suppress tumor growth and progression. Evidently, heme sequestration can be a powerful strategy for suppressing lung tumors and likely drug-resistant tumors that rely on oxidative phosphorylation for survival.



Biology, Molecular, Biology, Cell