AMPK and PKA interaction in the regulation of survival of liver cancer cells subjected to glucose starvation

Ferretti, Anabela C.; Tonucci, Facundo M.; Hidalgo, Florencia; Almada, Evangelina; Larocca, M. Cecilia; Favre, Cristián

doi:10.18632/oncotarget.7404

Cited by 59 publications

(52 citation statements)

References 45 publications

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“…This also highlights the potential importance of the RIα holoenzyme as a stress-responsive holoenzyme; it is not required when energy levels are high. The ATP-dependent holoenzyme activation allows the PKA holoenzyme to serve as an energy sensor, which is consistent with recent studies showing that PKA can be activated more by metabolic stress, such as glucose deprivation, than by cAMP stimulation; lowering the energy levels may be sufficient to influence PKA activation (52). Since the second Mg 2+ ion is essential for the high-affinity ATP binding to the RIα holoenzyme, we hypothesize that this holoenzyme can be also tightly regulated by metal homeostasis in cells (53,54).…”

Section: Discussionsupporting

confidence: 89%

Two PKA RIα holoenzyme states define ATP as an isoform-specific orthosteric inhibitor that competes with the allosteric activator, cAMP

Aoto

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Protein kinase A (PKA) holoenzyme, comprised of a cAMP-binding regulatory (R)-subunit dimer and 2 catalytic (C)-subunits, is the master switch for cAMP-mediated signaling. Of the 4 R-subunits (RIα, RIβ, RIIα, RIIβ), RIα is most essential for regulating PKA activity in cells. Our 2 RIα2C2 holoenzyme states, which show different conformations with and without ATP, reveal how ATP/Mg2+ functions as a negative orthosteric modulator. Biochemical studies demonstrate how the removal of ATP primes the holoenzyme for cAMP-mediated activation. The opposing competition between ATP/cAMP is unique to RIα. In RIIβ, ATP serves as a substrate and facilitates cAMP-activation. The isoform-specific RI-holoenzyme dimer interface mediated by N3A–N3A′ motifs defines multidomain cross-talk and an allosteric network that creates competing roles for ATP and cAMP. Comparisons to the RIIβ holoenzyme demonstrate isoform-specific holoenzyme interfaces and highlights distinct allosteric mechanisms for activation in addition to the structural diversity of the isoforms.

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Section: Discussionsupporting

confidence: 89%

Two PKA RIα holoenzyme states define ATP as an isoform-specific orthosteric inhibitor that competes with the allosteric activator, cAMP

Aoto

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…PKA, the cAMP-dependent protein kinase, has been shown to be activated by energy stress. 6,22 Moreover, Chang et al have shown that PKA interacts and phosphorylates DRP1 at S637, leading to mitochondrial elongation in HeLa cells. 23 Similar results have also been observed in non-transformed cells, including MEF and HEK293 cells.…”

Section: Discussionmentioning

confidence: 99%

“…Ferretti et al have shown that AMPK, a crucial cellular energy sensor, interacts with PKA and regulates the survival of liver cancer cells during glucose starvation. 22 Therefore, whether PKA acts alone or works together with other kinases to promote DRP1 phosphorylation in HCC cells subjected to energy stress still needs further investigation. Except for nutrient deficiency, hypoxia is another important energy stress.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial elongation-mediated glucose metabolism reprogramming is essential for tumour cell survival during energy stress

Huang

et al. 2017

Oncogene

106

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To date, mechanisms of tumour cell survival under energy stress are not well understood. Cumulative evidence is beginning to reveal that specific mitochondrial morphologies are often associated with energetic states and survival of cells. However, the functional roles of mitochondria in the metabolic adaptation of tumour cells to energy stress remain to be elucidated. In this study, we first investigated the changes in mitochondrial morphology induced by nutrition deprivation in tumour cells, and the underlying molecular mechanism. We then systematically explored glucose metabolism reprogramming by energy stress-induced alteration of mitochondrial morphology and its effect on tumour cell survival. Our results showed that starvation treatment resulted in a dramatic mitochondrial elongation, which was mainly mediated by DRP1 phosphorylation through protein kinase A activation and subsequent suppression of mitochondrial translocation of DRP1. We further observed that tumour cells under an energy stress condition exhibited a clear shift from glycolysis towards oxidative phosphorylation, which was reversed by the recovery of mitochondrial fission induced by forced expression of mutant DRP1. Mechanistically, energy stress-induced mitochondrial elongation facilitated cristae formation and assembly of respiratory complexes to enhance oxidative phosphorylation, which in turn exhibited a feedback inhibitory effect on glycolysis through NAD-dependent SIRT1 activation. In addition, our data indicated that DRP1-mediated mitochondrial elongation under energy stress was essential for tumour cell survival both in vitro and in vivo and predicted poor prognosis of hepatocellular carcinoma patients. Overall, our study demonstrates that remodelling of mitochondrial morphology plays a critical role in tumour cell adaptation to energy stress by reprogramming glucose metabolism.

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“…However, they did not consider the effects of p53 in their research. It has been reported that the metabolic environmental conditions and pathways that activate AMPK differentially regulate cell proliferation or viability in cancer and normal cells (19,54). Only a few studies have reported on the highly complex interrelationship between p53 and AMPK in cell death.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory role of AMP‑activated protein kinase in necroptosis of HCT116 colon cancer cells with p53 null mutation under nutrient starvation

Jung

Quynh

et al. 2018

Int J Oncol

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Simultaneous induction of other types of programmed cell death, alongside apoptosis, in cancer cells may be considered an attractive strategy for the development of more effective anticancer therapies. The present study aimed to investigate the role of AMP-activated protein kinase (AMPK) in nutrient/serum starvation-induced necroptosis, which is a programmed form of necrosis, in the presence or absence of p53. The present study detected higher cell proliferation and lower cell death rates in the HCT116 human colon cancer cell line containing a p53 null mutation (HCT116 p53 -/-) compared with in HCT116 cells harboring wild-type p53 (HCT116 p53 +/+ ), as determined using a cell viability assay. Notably, western blot analysis revealed a relatively lower level of necroptosis in HCT116 p53 -/cells compared with in HCT116 p53 +/+ cells. Investigating the mechanism, it was revealed that necroptosis may be induced in HCT116 p53 +/+ cells by significantly increasing reactive oxygen species (ROS) and decreasing mitochondrial membrane potential (MMP), whereas little alterations were detected in HCT116 p53 -/cells. Unexpectedly, a much lower level of ATP was detected in HCT116 p53 -/cells compared with in HCT116 p53 +/+ cells. Accordingly, AMPK phosphorylation on the Thr172 residue was markedly increased in HCT116 p53 -/cells. Furthermore, western blot analysis and ROS measurements indicated that AMPK inhibition, using dorsomorphin dihydrochloride, accelerated necroptosis by increasing ROS generation in HCT116 p53 -/cells. However, AMPK activation by AICAR did not suppress necroptosis in HCT116 p53 +/+ cells. In conclusion, these data strongly suggested that AMPK activation may be enhanced in HCT116 p53 -/cells under serum-depleted conditions via a drop in cellular ATP levels. In addition, activated AMPK may be at least partially responsible for the inhibition of necroptosis in HCT116 p53 -/cells, but not in HCT116 p53 +/+ cells.

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AMPK and PKA interaction in the regulation of survival of liver cancer cells subjected to glucose starvation

Cited by 59 publications

References 45 publications

Two PKA RIα holoenzyme states define ATP as an isoform-specific orthosteric inhibitor that competes with the allosteric activator, cAMP

Two PKA RIα holoenzyme states define ATP as an isoform-specific orthosteric inhibitor that competes with the allosteric activator, cAMP

Mitochondrial elongation-mediated glucose metabolism reprogramming is essential for tumour cell survival during energy stress

Inhibitory role of AMP‑activated protein kinase in necroptosis of HCT116 colon cancer cells with p53 null mutation under nutrient starvation

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