p66Shc signaling is involved in stress responses elicited by anthracycline treatment of rat cardiomyoblasts

Abstract

The adaptor protein p66Shc modulates cellular redox status integrating oxidative stress with mitochondrial stress responses. Upon oxidative stress, p66Shc is translocated to mitochondria or mitochondria-associated membranes in a multi-step process, resulting in locally increased reactive oxygen species production. This signaling pathway is believed to be important in the context of drug-induced organ toxicity. The use of anthracyclines as anticancer agents is limited due to a dose-dependent and cumulative toxicity resulting in cardiomyopathy. Treatment with the anthracycline doxorubicin (DOX) results in a dose-dependent and cumulative cardiotoxicity which is mediated, at least in part, by increased oxidative stress. In the present study, we investigated for the first time whether p66Shc signaling is activated during DOX treatment of the rat cardiomyoblast H9c2 cell line. We further tested whether the transcriptional factor FoxO3a, which activates target genes responsible for apoptosis and cell cycle arrest, is also involved in p66Shc-dependent redox signaling pathway. Our results suggest that DOX treatment induces p66Shc protein up-regulation specifically in nuclear fractions. Increased nuclear expression of FoxO3a was also detected in H9c2 cells after DOX treatment. Treatment with the antioxidant and protein kinase C (PKC-β) inhibitor hispidin decreased DOX-induced activation of caspase 9 and p66Shc alterations. Taking together, we hypothesize that p66Shc signaling is involved in the activation of stress/toxicity responses elicited by the treatment of H9c2 cells with DOX. Hence, the selective inhibition of this redox pathway may be a promising therapeutic approach to circumvent DOX cardiotoxicity.

Hispidin induces autophagic and necrotic death in SGC-7901 gastric cancer cells through lysosomal membrane permeabilization by inhibiting tubulin polymerization

“…On the other hand, hispidin was found to protect H9c2 cardiomyoblast cells against hydrogen peroxide-induced apoptosis by reducing intracellular ROS production and activating the Akt/GSK-3β and ERK1/2 signaling pathways [9]. Hispidin treatment decreased the doxorubicin-induced activation of caspase 9 and p66Shc alterations in H9c2 cardiomyoblast cells, thus providing a promising therapeutic approach for circumventing doxorubicin-induced cardiotoxicity [10]. Since hispidin seemed to play different roles under these conditions mentioned above, further research on how hispidin affects normal and cancer cells may help to treat cancer and to prevent chemotherapy-induced side effects.…”

Small molecule compounds alleviate anisomycin-induced oxidative stress injury in SH-SY5Y cells via downregulation of p66shc and Aβ1–42 expression

“…Previous studies have associated the loss of p66shc with reduced levels of reactive oxygen species and oxidative stress responses in the brain, improved spatial learning and memory, and prevention of ageing-induced behavioral changes (7)(8)(9)(10)(11)(12)(13)20,21). In addition, p66shc has been associated with an increased lifespan, which is predominantly reflected in the reduction of brain atrophy, the maintenance of behavioral plasticity and the increase in the overall level of brain-derived neurotrophic factor (22).…”

“…In addition, oxidative stress and ageing promote Aβ production, which has been associated with the occurrence of AD (5). The p66shc adaptor protein is important for the regulation of cellular senescence and oxidative stress (6)(7)(8)(9)(10)(11)(12); under oxidative stress, the brain is more susceptible to damage, as compared with other tissues and organs. In the early stages of AD, oxidative stress occurs prior to the appearance of pathological characteristics, and accelerates neurodegeneration and Aβ formation; thus suggesting that oxidative stress may be involved in the neuropathological process of AD (1)(2)(3)(4)(5)(6).…”

Klotho Deficiency Aggravated Diabetes-induced Podocyte injury

“…Nonetheless, the mechanisms of Klotho Podocyte is nonrenewable and vulnerable to a variety of injuries as is highly specialized, terminally differentiated epithelial cells that line the outer surface of the glomerular basement membrane 26 − 28 . Enhanced production of reactive oxygen species (ROS) has been recognized as the major determinant of age-related endothelial dysfunction 29,30 . p66SHC induced by HG could mediate mitochondrial dysfunction 12,31,32 . However, our study focused on diabetes-induced DNA damage that may be the root cause of podocyte damage.…”