Platelets Promote Mitochondrial Uncoupling and Resistance to Apoptosis in Leukemia Cells: A Novel Paradigm for the Bone Marrow Microenvironment

Abstract

Here we report that leukemia cell lines and primary CD34+ leukemic blasts exposed to platelet rich plasma (PRP) or platelet lysates (PL) display increased resistance to apoptosis induced by mitochondria-targeted agents ABT-737 and CDDO-Me. Intriguingly, leukemia cells exposed to platelet components demonstrate a reduction in mitochondrial membrane potential (ΔΨM) and a transient increase in oxygen consumption, suggestive of mitochondrial uncoupling. Accompanying the ranolazine-sensitive increase in oxygen consumption, a reduction in triglyceride content was also observed in leukemia cells cultured with platelet components indicating that lipolysis and fatty acid oxidation may support the molecular reduction of oxygen in these cells. Mechanistically, platelet components antagonized Bax oligomerization in accordance with previous observations supporting an antiapoptotic role for fatty acid oxidation in leukemia cells. Lastly, substantiating the notion that mitochondrial uncoupling reduces oxidative stress, platelet components induced a marked decrease in basal and rotenone-induced superoxide levels in leukemia cells. Taken together, the decrease in ΔΨM, the transient increase in ranolazine-sensitive oxygen consumption, the reduction in triglyceride levels, and the reduced generation of superoxide, all accompanying the increased resistance to mitochondrial apoptosis, substantiate the hypothesis that platelets may contribute to the chemoprotective sanctuary of the bone marrow microenvironment via promotion of mitochondrial uncoupling.

Platelets at the interface of thrombosis, inflammation, and cancer

“…59 Platelets and platelet lysates reduce apoptosis of leukemia cell lines and primary leukemic blasts induced by mitochondria-damaging agents. 60 Contents of platelet microparticles inhibited intrinsic apoptosis through mitochondrial uncoupling, independent of autophagy. 60 These are some of the first studies to extend the antiapoptotic role of platelets beyond solid tumors.…”

“…60 Contents of platelet microparticles inhibited intrinsic apoptosis through mitochondrial uncoupling, independent of autophagy. 60 These are some of the first studies to extend the antiapoptotic role of platelets beyond solid tumors. The results highlight the need for future studies to investigate the platelet's roles in both hematopoietic and solid tumor malignancies and in disrupting cellular energetics and metabolism related to apoptosis.…”

The Landscape of Circulating Tumor Cell Research in the Context of Epithelial-Mesenchymal Transition

“…Platelets seem to be of special importance for metastasis, since thrombocytosis is frequently observed in patients with metastatic cancers [58] . Platelets facilitate invasion of cancer cells, intra-and extravasation of CTCs (by secreting lysophosphatidic acid) [59,60] , protect them from various host attacks, such as immune assaults [61,62] , apoptosis [63,64] and shear stress [57,65,66] . Importantly, platelets may also contribute to EMT of CTCs and more efficient metastases formation [67] .…”

The Role of TRP Channels in the Metastatic Cascade

“…Within the bloodstream, circulating tumor cells (CTCs) interact with different blood cells such as platelets [ 12 ]. Platelet-CTC interactions seem to increase CTC survival, extravasation and metastasis [ 13 , 14 ]. Surviving CTCs adhere to endothelial cells lining the vessels, migrate intravascularly and penetrate the endothelial cell layer (extravasation).…”