Abstract
Platelets can modulate cancer through budding of platelet microparticles (PMPs) that can transfer a plethora of bioactive molecules to cancer cells upon internalization. In acute myelogenous leukemia (AML) this can induce chemoresistance, partially through a decrease in cell activity. Here we investigated if the internalization of PMPs protected the monocytic AML cell line, THP-1, from apoptosis by decreasing the initial cellular damage inflicted by treatment with daunorubicin, or via direct modulation of the apoptotic response. We examined whether PMPs could protect against apoptosis after treatment with a selection of inducers, primarily associated with either the intrinsic or the extrinsic apoptotic pathway, and protection was restricted to the agents targeting intrinsic apoptosis. Furthermore, levels of daunorubicin-induced DNA damage, assessed by measuring gH2AX, were reduced in both 2N and 4N cells after PMP co-incubation. Measuring different BCL2-family proteins before and after treatment with daunorubicin revealed that PMPs downregulated the pro-apoptotic PUMA protein. Thus, our findings indicated that PMPs may protect AML cells against apoptosis by reducing DNA damage both dependent and independent of cell cycle phase, and via direct modulation of the intrinsic apoptotic pathway by downregulating PUMA. These findings further support the clinical relevance of platelets and PMPs in AML.
Highlights
Platelets were originally discovered in the late 19th century as a key player in hemostasis [1]
These bioactive molecules can be transferred via platelet microparticles (PMPs), which in turn have been shown to be internalized by many different cancer cells, altering crucial functions of the cells, namely invasiveness, proliferation, and viability [18,19,20]
We have previously demonstrated that PMPs increase resistance to DNR-induced apoptosis and cell death [52]
Summary
Platelets were originally discovered in the late 19th century as a key player in hemostasis [1]. Apoptosis can be divided into two separate pathways, which are interlinked with common feedback mechanisms [40]; the death receptor initiated extrinsic pathway (FAS/CD95, TNFR1, TRAIL-R1, TRAIL-R2, DR3, and DR6), and the intrinsic, or mitochondrial, pathway. Dysregulation of the latter has proven to be an important feature in cancer biology [41]. Whether the PMP-associated increase in resistance to DNR is caused solely by protection against DNR-induced cell damage, or a modulation of the intrinsic apoptotic pathway regulators, remains unknown. We sought to further examine the anti-apoptotic effects of PMPs in the monocytic AML cell line THP-1
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