Protein Carbonylation and Lipid Peroxidation in Hematological Malignancies

Abstract

Among the different mechanisms involved in oxidative stress, protein carbonylation and lipid peroxidation are both important modifications associated with the pathogenesis of several diseases, including cancer. Hematopoietic cells are particularly vulnerable to oxidative damage, as the excessive production of reactive oxygen species and associated lipid peroxidation suppress self-renewal and induce DNA damage and genomic instability, which can trigger malignancy. A richer understanding of the clinical effects of oxidative stress might improve the prognosis of these diseases and inform therapeutic strategies. The most common protein carbonylation and lipid peroxidation compounds, including hydroxynonenal, malondialdehyde, and advanced oxidation protein products, have been investigated for their potential effect on hematopoietic cells in several studies. In this review, we focus on the most important protein carbonylation and lipid peroxidation biomarkers in hematological malignancies, their role in disease development, and potential treatment implications.

Keywords: hematological malignancies; lipid peroxidation; oxidative stress; protein carbonylation.

Figure 1

(a) The most common mechanisms of protein carbonylation. Direct processes include reactive oxygen species (ROS) attack, metal-catalyzed oxidation (MCO), and by oxidative cleavage of protein backbone (via the α-amidation pathway or through oxidation of glutamine side chains). The indirect mechanisms involve the reaction with (b) advanced glycation end-products (AGEs) and (c) advanced lipid peroxidation end-products (ALEs).

Figure 2

Protein carbonylation can induce membrane glycoprotein desialylation in platelets of patients with Hodgkin lymphoma. The level of sialic acid residues in platelets was found to be significantly lower and the carbonylation of proteins was higher in 10 cases of Hodgkin lymphoma compared with healthy controls [78]. A positive correlation was observed between the carbonylation of platelet proteins and the reduction in the content of N-acetyl neuraminic acid (NANA, a sialic acid residue) in platelet membrane glycoproteins, whose removal is involved in different physiological processes. The role of protein carbonylation in desialytation remains to be elucidated.

Figure 3

Oxidative damage in transfusion-dependent patients with MDS. Frequent transfusions in patients with MDS leads to iron overload in serum, which plays a key role in the generation of highly reactive oxygen species (ROS) [135]. The increase of ROS could directly oxidize proline (Pro), Arginine (Arg), Lysine (Lys), and Threonine (Thr) residues. ROS-induced lipid peroxidation of long-chain polyunsaturated fatty acids (PUFAs) also promotes protein carbonylation by reaction with lipid peroxidation end-products such as malondialdehyde (MDA) and 4-hydroxy-2-nonenal (HNE).

Figure 4

Oxidative stress modulators for the treatment of hematological malignancies. Several antioxidants such as resveratrol, melatonin, and curcumin exert both antioxidant and pro-oxidant activities. By modulating different antioxidant enzymes and transcription factors (TFs), these compounds reduce protein carbonylation and/or lipid peroxidation and inhibit tumor progression. They present cytotoxic effects by enhancing reactive oxygen species (ROS) production. Iron chelators such as deferasirox (DFX) inhibit ROS production directly or indirectly by suppressing the active redox forms of iron and regulating mitochondrial activity and can significantly decrease lipid peroxidation and protein carbonylation in a mechanism dependent on the cell cycle and p21. It will be interesting to explore whether DFX exerts its control on p21 through NF-κB [145] or by inhibiting signaling pathways activated by oxidative stress that control the cell cycle via p53 [146]. COX, cyclooxygenase; LO, lipoxygenase; MM, multiple myeloma; NOS, nitric oxide synthase.