Recent Advances in EPAC-Targeted Therapies: A Biophysical Perspective

Ahmed, Alveena; Boulton, Stephen; Shao, Hongzhao; Akimoto, Madoka; Natarajan, Amarnath; Cheng, Xiaodong; Melacini, Giuseppe

doi:10.3390/cells8111462

Cited by 20 publications

(16 citation statements)

References 95 publications

(236 reference statements)

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“…2E). Treatment with ESI-09, an Epac inhibitor (Ahmed et al , 2019), significantly inhibited Tpcn2 mRNA expression at 2 hours and this effect continued to the 4 hour time point (Fig. 2F).…”

Section: Resultsmentioning

confidence: 88%

Two-pore channel 2 is a key regulator of adipocyte differentiation via the cAMP signaling pathway with calpain as downstream effector

Zhang

Chan

Tunn

et al. 2021

Preprint

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We investigated whether the endolysosomal two-pore channel TPC2 is a mediator of adipocyte differentiation. We show that Tpcn2 mRNA is expressed transiently during induction of C3H10T1/2 mesenchymal stem cells to differentiate into adipocytes, and that this expression is triggered by cAMP. This is the first demonstration of a cell signaling pathway that can regulate TPC gene expression. We also identified an important functional role for TPC2 in adipocyte differentiation. First, ectopic TPC2 expression in C3H10T1/2 cells partially rescued the block to adipocyte differentiation caused by cAMP absence. Second, inhibition of endogenous TPC2 expression in primary preadipocytes substantially reduced their ability to differentiate into adipocytes. Finally, genetic variation at the Tpcn2 locus is associated with increased upper-body fat distribution in women concomitant with reduced Tpcn2 expression in abdominal adipose tissue. Our findings implicate TPC2 as an important mediator of adipogenesis and may aid identification of new drug targets for treatment of obesity.

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“…2E). Treatment with ESI-09, an Epac inhibitor (Ahmed et al , 2019), significantly inhibited Tpcn2 mRNA expression at 2 hours and this effect continued to the 4 hour time point (Fig. 2F).…”

Section: Resultsmentioning

confidence: 88%

Two-pore channel 2 is a key regulator of adipocyte differentiation via the cAMP signaling pathway with calpain as downstream effector

Zhang

Chan

Tunn

et al. 2021

Preprint

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“…This site falls on the interface between the two CNBDs that Epac2 possesses; meanwhile, it is absent in Epac1 due to the presence of one CNBD only. Binding of ESI-05 or ESI-07 to this domain locks Epac2 in its inactive state described previously [152].…”

Section: Implication Of Epac Modulators In Cancer Therapymentioning

confidence: 67%

The Role of Epac in Cancer Progression

Wehbe

Slika

Mesmar

et al. 2020

IJMS

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Cancer continues to be a prime contributor to global mortality. Despite tremendous research efforts and major advances in cancer therapy, much remains to be learned about the underlying molecular mechanisms of this debilitating disease. A better understanding of the key signaling events driving the malignant phenotype of cancer cells may help identify new pharmaco-targets. Cyclic adenosine 3′,5′-monophosphate (cAMP) modulates a plethora of biological processes, including those that are characteristic of malignant cells. Over the years, most cAMP-mediated actions were attributed to the activity of its effector protein kinase A (PKA). However, studies have revealed an important role for the exchange protein activated by cAMP (Epac) as another effector mediating the actions of cAMP. In cancer, Epac appears to have a dual role in regulating cellular processes that are essential for carcinogenesis. In addition, the development of Epac modulators offered new routes to further explore the role of this cAMP effector and its downstream pathways in cancer. In this review, the potentials of Epac as an attractive target in the fight against cancer are depicted. Additionally, the role of Epac in cancer progression, namely its effect on cancer cell proliferation, migration/metastasis, and apoptosis, with the possible interaction of reactive oxygen species (ROS) in these phenomena, is discussed with emphasis on the underlying mechanisms and pathways.

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“…ESI-09 and HJC0197 have been identified in high-throughput screening as specific competitive inhibitors that target the cAMP-binding domain of EPAC/cAMP-guanine exchange factor (GEF) [ [49] , [50] , [51] , [52] , [53] , [54] ] ( Supplementary Fig. S2 ).…”

Section: Discussionmentioning

confidence: 99%

Anti-cancer strategy targeting the energy metabolism of tumor cells surviving a low-nutrient acidic microenvironment

Maeda

Kikuchi

Kawagoe

et al. 2020

Molecular Metabolism

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Objective Tumor cells experience hypoxia, acidosis, and hypoglycemia. Metabolic adaptation to glucose shortage is essential to maintain tumor cells’ survival because of their high glucose requirement. This study evaluated the hypothesis that acidosis might promote tumor survival during glucose shortage and if so, explored a novel drug targeting metabolic vulnerability to glucose shortage. Methods Cell survival and bioenergetics metabolism were assessed in lung cancer cell lines. Our in-house small-molecule compounds were screened to identify those that kill cancer cells under low-glucose conditions. Cytotoxicity against non-cancerous cells was also assessed. Tumor growth was evaluated in vivo using a mouse engraft model. Results Acidosis limited the cellular consumption of glucose and ATP, causing tumor cells to enter a metabolically dormant but energetically economic state, which promoted tumor cell survival during glucose deficiency. We identified ESI-09, a previously known exchange protein directly activated by cAMP (EAPC) inhibitor, as an anti-cancer compound that inhibited cancer cells under low-glucose conditions even when associated with acidosis. Bioenergetic studies showed that independent of EPAC inhibition, ESI-09 was a safer mitochondrial uncoupler than a classical uncoupler and created a futile cycle of mitochondrial respiration, leading to decreased ATP production, increased ATP dissipation, and fuel scavenging. Accordingly, ESI-09 exhibited more cytotoxic effects under low-glucose conditions than under normal glucose conditions. ESI-09 was also more effective than actively proliferating cells on quiescent glucose-restricted cells. Cisplatin showed opposite effects. ESI-09 inhibited tumor growth in lung cancer engraft mice. Conclusions This study highlights the acidosis-induced promotion of tumor survival during glucose shortage and demonstrates that ESI-09 is a novel potent anti-cancer mitochondrial uncoupler that targets a metabolic vulnerability to glucose shortage even when associated with acidosis. The higher cytotoxicity under lower-than-normal glucose conditions suggests that ESI-09 is safer than conventional chemotherapy, can target the metabolic vulnerability of tumor cells to low-glucose stress, and is applicable to many cancer cell types.

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Recent Advances in EPAC-Targeted Therapies: A Biophysical Perspective

Cited by 20 publications

References 95 publications

Two-pore channel 2 is a key regulator of adipocyte differentiation via the cAMP signaling pathway with calpain as downstream effector

Two-pore channel 2 is a key regulator of adipocyte differentiation via the cAMP signaling pathway with calpain as downstream effector

The Role of Epac in Cancer Progression

Anti-cancer strategy targeting the energy metabolism of tumor cells surviving a low-nutrient acidic microenvironment

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