Essential Opposite Roles of ERK and Akt Signaling in Cardiac Steroid-Induced Increase in Heart Contractility

Buzaglo, Nahum; Rosen, Haim; Ami, Hagit Cohen Ben; Inbal, Adi; Lichtstein, David

doi:10.1124/jpet.115.230763

Cited by 6 publications

(3 citation statements)

References 37 publications

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“…For example, MAPK/ERK signaling inhibited EGFR/PI3`K/AKT-mediated tissue factor (an initiator of blood coagulation and a participant in cancer progression and metastasis) expression in MDA-MB-231 cells [66]. Moreover, AKT inhibits MAPK’s role in the steroid-induced increase of heart muscle contractility [67]. Finally, inhibiting the AKT pathway, while activating the ERK pathway, contributes to neuronal apoptosis [68].…”

Section: Discussionmentioning

confidence: 99%

The pro- and anti-tumor roles of mesenchymal stem cells toward BRCA1-IRIS-overexpressing TNBC cells

et al. 2019

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Background To evaluate the cross-talk between BRCA1-IRIS (IRIS)-overexpressing (IRISOE) TNBC cells and tumor-resident mesenchymal stem cells (MSCs) that triggers the aggressiveness or elimination of IRISOE TNBC tumors. Methods We analyzed the effect of silencing or inactivating IRIS on the bi-directional interaction between IRISOE TNBC cells and MSCs on tumor formation and progression. We analyzed the downstream signaling in MSCs induced by IL-6 secreted from IRISOE TNBC cells. We compared the effect of MSCs on the formation and progression of IRIS-proficient and deficient-TNBC cells/tumors using in vitro and in vivo models. Finally, we analyzed the association between IL-6, PTGER2, and PTGER4 overexpression and breast cancer subtype; hormone receptor status; and distant metastasis-free or overall survival. Results We show high-level IL-6 secreted from IRISOE TNBC cells that enhances expression of its receptor (IL-6R) in MSCs, their proliferation, and migration toward IRISOE, in vitro, and recruitment into IRISOE TNBC tumors, in vivo. In serum-free medium, recombinant IL-6 and the IL-6-rich IRISOE TNBC cell condition media (CM) decreased STAT3 Y705 phosphorylation (p-STAT3 Y705 ) in MSCs. Inhibiting IRIS expression or activity prolonged STAT3 Y705 phosphorylation in MSCs. The interaction with IRISOE TNBC cells skewed MSC differentiation toward prostaglandin E 2 (PGE 2 )-secreting pro-aggressiveness cancer-associated fibroblasts (CAFs). Accordingly, co-injecting human or mouse MSCs with IRISOE TNBC tumor cells promoted the formation of aggressive mammary tumors, high circulating IL-6 and PGE 2 levels, and reduced overall survival. In contrast, IRIS-silenced or inactivated cells showed reduced tumor formation ability, limited MSC recruitment into tumors, reduced circulating IL-6 and PGE 2 levels, and prolonged overall survival. A positive correlation between IL-6, PTGER2, and PTGER4 expression and basal phenotype; ER-negativity; distant metastasis-free and overall survival in basal; or BRCA mutant carriers was observed. Finally, the bi-directional interaction with MSCs triggered death rather than growth of IRIS-silenced TNBC cells, in vitro and in vivo. Conclusions The IL-6/PGE 2 -positive feedback loop between IRISOE TNBC tumor cells and MSCs enhances tumor aggressiveness. Inhibiting IRIS expression limits TNBC tumor growth and progression through an MSC-induced death of IRIS-silenced/inactivated TNBC cells. Electronic supplementary material The online version of this article (10.1186/s13058-019-1131-2) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

The pro- and anti-tumor roles of mesenchymal stem cells toward BRCA1-IRIS-overexpressing TNBC cells

et al. 2019

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“…It is tempting to propose that the alterations in ERK and Akt phosphorylation caused by changes in ECS are mediated by their interactions with Na + , K + -ATPase. Such a sequence of events was proposed for the CS-induced effects on stimulation of cell viability [102], increased heart contractility [103,104], and kidney development [105]. …”

Section: Na+ K+-atpase Signaling and Bdmentioning

confidence: 99%

Na+, K+-ATPase Signaling and Bipolar Disorder

Lichtstein¹,

Ilani²,

Rosen³

et al. 2018

IJMS

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Bipolar disorder (BD) is a severe and common chronic mental illness characterized by recurrent mood swings between depression and mania. The biological basis of the disease is poorly understood and its treatment is unsatisfactory. Although in past decades the “monoamine hypothesis” has dominated our understanding of both the pathophysiology of depressive disorders and the action of pharmacological treatments, recent studies focus on the involvement of additional neurotransmitters/neuromodulators systems and cellular processes in BD. Here, evidence for the participation of Na+, K+-ATPase and its endogenous regulators, the endogenous cardiac steroids (ECS), in the etiology of BD is reviewed. Proof for the involvement of brain Na+, K+-ATPase and ECS in behavior is summarized and it is hypothesized that ECS-Na+, K+-ATPase-induced activation of intracellular signaling participates in the mechanisms underlying BD. We propose that the activation of ERK, AKT, and NFκB, resulting from ECS-Na+, K+-ATPase interaction, modifies neuronal activity and neurotransmission which, in turn, participate in the regulation of behavior and BD. These observations suggest Na+, K+-ATPase-mediated signaling is a potential target for drug development for the treatment of BD.

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“…Conversely, the positive inotropic effect, as well as the anti-cancer and anti-viral effects, are largely a result of the CS-induced signaling activation. Indeed, the inhibition of ERK activation totally prevented the bufalin and other CS-induced increase in heart contractility [ 15 ]; the bufalin anti-cancer effect was shown repeatedly to be mediated by ERK and AKT signaling [ 16 ], as was the anti-viral activity of CS [ 17 ]. It is reasonable to suggest, therefore, that differences in CS-induced signaling by various CS will have a profound effect on their pharmacological profiles.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Biological Evaluation of Novel Bufalin Derivatives

Sampath¹,

Horesh²,

Sasi³

et al. 2022

IJMS

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Bufalin and other cardiac steroids (CS) have been used for centuries for the treatment of congestive heart failure, arrhythmias, and other maladies. However, toxicity and the small therapeutic window of this family of steroids limit their use. Therefore, attempts to synthesize a potent, but less toxic, CS are of major importance. In the present study, two novel bufalin derivatives were synthesized and some of their pharmacological properties were characterized. The reaction of bufalin with Ishikawa’s reagent resulted in the production of two novel bufalin derivatives: bufalin 2,3-ene and bufalin 3,4-ene. The compounds were purified with TLC and HPLC and their structure was verified with UV, NMR, and MS analyses. The biological activities of these compounds were evaluated by testing their ability to inhibit the Na+, K+-ATPase activity of the brain microsomal fraction to induce cytotoxic activity against the NCI-60 human tumor cell line panel and non-cancer human cells, and to increase the force of contraction of quail embryonic heart muscle cells in culture. The two steroids exhibited biological activities similar to those of other CS in the tested experimental systems, but with reduced cytotoxicity, advocating their development as drugs for the treatment of heart failure and arrhythmias.

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Essential Opposite Roles of ERK and Akt Signaling in Cardiac Steroid-Induced Increase in Heart Contractility

Cited by 6 publications

References 37 publications

The pro- and anti-tumor roles of mesenchymal stem cells toward BRCA1-IRIS-overexpressing TNBC cells

The pro- and anti-tumor roles of mesenchymal stem cells toward BRCA1-IRIS-overexpressing TNBC cells

Na+, K+-ATPase Signaling and Bipolar Disorder

Synthesis and Biological Evaluation of Novel Bufalin Derivatives

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