Doxorubicin induced ROS-dependent HIF1α activation mediates blockage of IGF1R survival signaling by IGFBP3 promotes cardiac apoptosis

Abstract

Doxorubicin (Dox) causes the generation of intracellular reactive oxygen species (ROS) and inactivates insulinlike growth factor 1 (IGF1) signaling, leading to cardiomyocyte apoptosis. IGF-binding protein 3 (IGFBP3) is the most abundant circulating IGF1 carrier protein with high affinity, which has been reported to mediate ROSinduced apoptosis. Hypoxia-inducible factor 1α (HIF1A), an upstream protein of IGFBP3 is regulated by prolyl hydroxylase domain (PHD) through hydroxylation. In this study, we investigated the role of IGFBP3, HIF1A, and PHD in Dox-induced cardiac apoptosis. Cells challenged with 1 μM Dox for 24 h increased ROS generation, augmented intracellular and secreted IGFBP3 levels, and reduced IGF1 signaling. Further, we showed that Dox enhanced the extracellular association of IGF1 with IGFBP3. Moreover, echocardiography parameters, especially ejection fraction (EF) and fractional shortening (FS) were significantly reduced in ventricle tissue of Dox challenged rats. Notably, siRNA approach against IGFBP3 or an anti-IGFBP3 antibody rescued Dox-induced cardiac apoptosis, mitochondrial ROS, and the www.aging-us.com

Single-molecule tracking-based drug screening

“…Some compounds were reported to interact with the plasma membrane to possibly alter EGFR mobility: daunorubicin presents cytotoxic effects by penetrating the membrane (31), eltrombopag binds to the transmembrane region of TpoR (32), and broxyquinoline introduces oxygen free radicals into the membrane. On the other hand, mechanisms involving more direct interactions with EGFR to reduce the mobility are suggested from the previous reports (33)(34)(35)(36). Fig.…”

“…Broxyquinoline stabilizes hypoxia inducible factor (HIF)-1 ( 33 ) to acutely accumulate caveolin-1 in the lipid raft to constitute caveolae ( 34 ), which directly interacts with EGFR and confines protein mobility. Daunorubicin generates reactive oxygen species (ROS) to stabilize HIF-1 ( 35 ), enabling a similar effect as broxyquinoline. Eltrombopag stabilizes syndecan (SCD)-4 ( 36 ), which can form a protein complex with EGFR and integrin α 5 β 1 ( 37 ).…”

Doxorubicin Attenuates Free Fatty Acid-Induced Lipid Accumulation via Stimulation of p53 in HepG2 Cells

“…Therefore, we examined the effect of doxorubicin-mediated p53 upregulation on FFA-induced ROS production. Notably, high-dose of doxorubicin can increase ROS generation and induces ROS-mediated senescence and lipid synthesis by overcoming the key function of p53 ( Wen et al ., 2023 ). Moreover, p53 knockdown-induced increase in ROS production suggests that non-toxic dose of doxorubicin might play an anti-oxidative role via p53 activation.…”

Oxidative Stress-Responsive Apoptosis Inducing Protein (ORAIP) Plays a Critical Role in Dextran Sulfate Sodium-Induced Murine Model of Ulcerative Colitis

“…It appears that in response to oxidative stress, ROS-mediated signaling rather than ORAIP-mediated signaling plays major roles in causing DNA damage that leads to carcinogenesis [36,37]. For doxorubicin-induced apoptosis in cardiac myocytes, it seems that both ROS-mediated and ORAIP-mediated apoptotic signaling contribute independently to the total cell injury induced by doxorubicin [32,38]. This is supported by our former findings that the anti-ORAIP mAb treatment was less effective in doxorubicin-induced apoptosis than that in high glucose-induced apoptosis, suggesting a bigger role of ROS in doxorubicin than in high glucose [32].…”