Nucleus-mitochondria positive feedback loop formed by ERK5 S496 phosphorylation-mediated poly (ADP-ribose) polymerase activation provokes persistent pro-inflammatory senescent phenotype and accelerates coronary atherosclerosis after chemo-radiation

Cancer treatment-induced NAD+ depletion in premature senescence and late cardiovascular complications

“…Endothelial cell senescence can cause endothelial dysfunction through dysregulation of vasodilation and hemostasis, inducing oxidative stress and inflammation and inhibition of angiogenesis, which are involved in IR-mediated late effects [ 76 ] . Doxorubicin and IR induce myeloid cell senescence by triggering metabolite changes with nicotinamide adenine dinucleotide (NAD) depletion and mitochondrial stunning [ 77 ] . Low doses of doxorubicin induce human primary vascular smooth muscle cells (VSMC) senescence through the mediation of TRF2 ubiquitination and proteasomal degradation [ 78 ] .…”

“…Our recent study revealed that in myeloid cells, NAD + is reduced after treatment with doxorubicin or IR. Specifically, we observed a sustained SASP induction and an upregulation of p90RSK-mediated ERK5 S496 phosphorylation as well as downstream inflammatory signaling pathways in myeloid cells treated with doxorubicin or IR [ 77 ] . To gain insight into the underlying molecular mechanism, we discovered that doxorubicin and IR activated poly (ADP-ribose) polymerase (PARP) and subsequent NAD + depletion.…”

“…Consequently, reversible mitochondrial dysfunction was mediated without inducing cell death even when ATP is depleted. We also noted that, although low-dose IR inhibited both oxidative phosphorylation (OXPHOS) and glycolysis without causing cellular necrosis or apoptosis, significant upregulation of mitochondrial ROS production and succinate production occurred, attesting to the metabolically active status of SASP [ 77 ] .…”

“…Telomere shortening and telomeric DNA damage induced by aging and cancer treatments can cause NAD + depletion by activating PARP [ 77 ] or increasing [ 169 ] CD38 expression [ 170 ] . PARP1 overactivation can lead to a catastrophic decrease of cytosolic NAD + and thereby directly inhibiting glycolysis and causing cell death [ 117 , 171 , 172 ] .…”

“…We also found that complex II activity is required for mitochondrial stunning-triggered mitochondrial ROS production. As such, sustained mitochondrial ROS production without killing the cells is critical for chronic inflammation and unceasing SASP status, which we noted even long after the completion of cancer therapy (late effects) [ 77 ] . A positive feedback loop formed by the p90RSK/ERK5-S496 inflammatory complex contributes to persistent SASP induction as (i) telomeric DNA damage to senescence; (ii) ERK5 S496 phosphorylation-NRF2 and PARP activation to inflammation and ROS [ 176 , 177 ] ; (iii) mitochondrial stunning to mitochondrial ROS; and (iv) p90RSK-ERK5 S496 phosphorylation to efferocytosis [ Figure 2 ] [ 176 ] .…”