Low-protein diet disrupts the crosstalk between the PKA and PKC signaling pathways in isolated pancreatic islets

Lippo, Bruno Rodrigo da Silva; Batista, Thiago M.; Rezende, Luiz F.; Cappelli, Ana Paula Gameiro; Camargo, Rafael Ludemann; Branco, Renato Chaves Souto; Barbosa-Sampaio, Helena Cristina; Wanderley, Maria Inês; Arantes, Vanessa Cristina; Corat, Marcus Alexandre Finzi; Carneiro, Everardo M.; Udrisar, Daniel P.; Wanderley, Almir Gonçalves; Ferreira, Fabiano

doi:10.1016/j.jnutbio.2014.12.010

Cited by 12 publications

(9 citation statements)

References 85 publications

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“…reported that heat treatment resulted in decreased food consumption and body weight gain [20], which is in agreement with our present findings. Several studies have demonstrated that a low-protein diet caused a decrease in body weight [1, 2, 25], but in the present study, there was no significant difference in body weight between the control and low-protein groups. In the above-cited studies, an approximately 6% protein diet was used as the low-protein diet, and the lower protein content could be responsible for the more significant effect of protein malnutrition compared to that observed in the present study, in which a 10% protein diet was used as the low-protein diet.…”

Section: Discussioncontrasting

confidence: 92%

“…Protein restriction has been reported to lead to an increase in energy expenditure and the activation of thermogenesis in brown adipose tissue, as evidenced by an increase in catecholamine levels [1]. Another study demonstrated that protein restriction caused a disruption in the crosstalk between the protein kinase A and protein kinase C signaling pathways and, consequently, in the secretory synergism in islets [2]. Protein malnutrition also affects adrenocortical stress response activity [3, 4, 5, 6, 7].…”

Section: Introductionmentioning

confidence: 99%

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Low-protein diet decreased the adrenal function and spontaneous activity of mice during chronic heat stress

Tsuda

Iwasawa

Yamaguchi

2019

Heliyon

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Protein restriction is a well-known risk factor that induces the deterioration of various biological functions. However, little is known about the effects of protein restriction on behavioral markers and the adrenal function of mice exposed to chronic stress. Here we evaluated the effects of a low-protein diet on the spontaneous activity and adrenal function of chronic heat-stressed mice. ICR mice were fed a control diet (20% protein) or a low-protein diet (10% protein) for 14 consecutive days. From the 10th day of the diet period, the mice were repeatedly exposed to a temperature condition of 35 ± 1 °C for 2 hr/day for four consecutive days. The spontaneous activities of the mice were estimated for the behavioral analysis. On the last day, we performed a blood collection test and an ACTH stimulation test for adrenal function analysis. For the blood collection test, mice were exposed to heat stress again for 2 hr, and blood was collected immediately after this heat stress. We measured the plasma levels of corticotropin releasing hormone, adrenocorticotropin (ACTH), and corticosterone. For the ACTH stimulation test, cosyntropin was intraperitoneally administered, and the plasma corticosterone levels were measured. The spontaneous activity of the low-protein mice was significantly lower than that of the control mice during the dark period of heat stress. The plasma corticosterone levels were greatly increased by heat stress, with no significant difference between the control and low-protein groups. The ACTH stimulation test revealed that the plasma corticosterone concentration of the heat-stressed low-protein mice was significantly lower than that of the heat-stressed controls. In conclusion, the low-protein diet decreased the spontaneous activity and the adrenal function of mice during heat stress, which implies that protein restriction during chronic heat stress induces fatigue by reducing the adrenal function.

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Section: Discussioncontrasting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Low-protein diet decreased the adrenal function and spontaneous activity of mice during chronic heat stress

Tsuda

Iwasawa

Yamaguchi

2019

Heliyon

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“…Several studies have shown that PKC is responsive to nutritional status (Lee et al 2008, Vary et al 2005, da Silva Lippo et al 2015). PKC exists in a variety of isotypes (i.e.…”

Section: Introductionmentioning

confidence: 99%

Increased IGFBP-1 phosphorylation in response to leucine deprivation is mediated by CK2 and PKC

Malkani

Biggar

Shehab

et al. 2016

Molecular and Cellular Endocrinology

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Insulin-like growth factor binding protein-1 (IGFBP-1), secreted by fetal liver, is a key regulator of IGF-I bioavailability and fetal growth. IGFBP-1 phosphorylation decreases IGF-I bioavailability and diminishes its growth-promoting effects. Growth-restricted fetuses have decreased levels of circulating essential amino acids. We recently showed that IGFBP-1 hyperphosphorylation (pSer101/119/169) in response to leucine deprivation is regulated via activation of the amino acid response (AAR) in HepG2 cells. Here we investigated nutrient-sensitive protein kinases CK2/PKC/PKA in mediating IGFBP-1 phosphorylation in leucine deprivation. We demonstrated that leucine deprivation stimulated CK2 activity (enzymatic assay) and induced IGFBP-1 phosphorylation (immunoblotting/MRM-MS). Inhibition (pharmacological/siRNA) of CK2/PKC, but not PKA, prevented IGFBP-1 hyperphosphorylation in leucine deprivation. PKC inhibition also prevented leucine deprivation-stimulated CK2 activity. Functionally, leucine deprivation decreased IGF-I-induced-IGF-1R autophosphorylation when CK2/PKC were not inhibited. Our data strongly support that PKC promotes leucine deprivation-induced IGFBP-1 hyperphosphorylation via CK2 activation, mechanistically linking decreased amino acid availability and reduced fetal growth.

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“…Furthermore, we have demonstrated previously that the markedly enhanced expression of protein kinase C (PKC) in SW480/tria cells contributes to ABCB1 overexpression [10]. Interestingly, strong evidence exists for a crosstalk between PKC and PKA-Creb signaling pathways [53] suggesting that PDE4D loss might play a role in ABCB1 overexpression in SW480/tria cells. Surprisingly, however, inhibition of PKA with H-89 did not significantly re-sensitize SW480/tria cells against triapine.…”

Section: Discussionmentioning

confidence: 99%

Loss of phosphodiesterase 4D mediates acquired triapine resistance via Epac-Rap1-Integrin signaling

et al. 2016

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Triapine, an anticancer thiosemicarbazone, is currently under clinical investigation. Whereas promising results were obtained in hematological diseases, trials in solid tumors widely failed. To understand mechanisms causing triapine insensitivity, we have analysed genomic alterations in a triapine-resistant SW480 subline (SW480/tria). Only one distinct genomic loss was observed specifically in SW480/tria cells affecting the phosphodiesterase 4D (PDE4D) gene locus. Accordingly, pharmacological inhibition of PDE4D resulted in significant triapine resistance in SW480 cells. Hence, we concluded that enhanced cyclic AMP levels might confer protection against triapine. Indeed, hyperactivation of both major downstream pathways, namely the protein kinase A (PKA)-cAMP response element-binding protein (Creb) and the exchange protein activated by cAMP (Epac)-Ras-related protein 1 (Rap1) signaling axes, was observed in SW480/tria cells. Unexpectedly, inhibition of PKA did not re-sensitize SW480/tria cells against triapine. In contrast, Epac activation resulted in distinct triapine resistance in SW480 cells. Conversely, knock-down of Epac expression and pharmacological inhibition of Rap1 re-sensitized SW480/tria cells against triapine. Rap1 is a well-known regulator of integrins. Accordingly, SW480/tria cells displayed enhanced plasma membrane expression of several integrin subunits, enhanced adhesion especially to RGD-containing matrix components, and bolstered activation/expression of the integrin downstream effectors Src and RhoA/Rac. Accordingly, integrin and Src inhibition resulted in potent triapine re-sensitization especially of SW480/tria cells. In summary, we describe for the first time integrin activation based on cAMP-Epac-Rap1 signaling as acquired drug resistance mechanism. combinations of triapine with inhibitors of several steps in this resistance cascade might be feasible strategies to overcome triapine insensitivity of solid tumors.

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Low-protein diet disrupts the crosstalk between the PKA and PKC signaling pathways in isolated pancreatic islets

Cited by 12 publications

References 85 publications

Low-protein diet decreased the adrenal function and spontaneous activity of mice during chronic heat stress

Low-protein diet decreased the adrenal function and spontaneous activity of mice during chronic heat stress

Increased IGFBP-1 phosphorylation in response to leucine deprivation is mediated by CK2 and PKC

Loss of phosphodiesterase 4D mediates acquired triapine resistance via Epac-Rap1-Integrin signaling

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