The metabolic/pH sensor soluble adenylyl cyclase is a tumor suppressor protein

Ramos‐Espiritu, Lavoisier; Díaz, Ana; Nardin, Charlée; Saviola, Anthony J.; Shaw, Fawwaz; Plitt, Tamar; Yang, Xia; Wolchok, Jedd D.; Pirog, Edyta C.; Desman, Garrett; Sboner, Andrea; Zhang, Tuo; Xiang, Jenny; Merghoub, Taha; Levin, Lonny R.; Buck, Jochen; Zippin, Jonathan H.

doi:10.18632/oncotarget.10056

Cited by 19 publications

(21 citation statements)

References 47 publications

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“…Although the baseline lactate-to-pyruvate ratios were different in each cell type, sAC inhibition always led to an elevated medium lactate-to-pyruvate ratio. These findings show that both pharmacological and genetic suppression of sAC activity promotes aerobic glycolysis under normoxic conditions, resembling the Warburg effect observed in many cancer cells and consistent with the previously observed tumor suppression effect of sAC (Ramos-Espiritu, Diaz et al, 2016a).…”

Section: Resultssupporting

confidence: 91%

“…In particular, the metabolic reprogramming in the sAC-suppressed state, namely increased glycolytic flux and cytosolic NADH/NAD + ratio with reduction in oxidative phosphorylation, resembles the seminal observation described by Otto Warburg that growing tumors utilized glucose by aerobic glycolysis despite sufficient oxygen tension for oxidative phosphorylation. This contention is supported by the observation that a large panel tumor samples have lower sAC expression than the corresponding normal tissues (Ramos-Espiritu et al, 2016a). Moreover, the recent development of NADH/NAD + biosensors confirms that transformed cells have in general an elevated cytosolic free NADH/NAD + ratio as compared to non-transformed cells (Schwartz, Passonneau et al, 1974, Zhao, Hu et al, 2015).…”

Section: Discussionmentioning

confidence: 90%

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Non-canonical regulation of glycogenolysis and the Warburg phenotype by soluble adenylyl cyclase

Chang

Gilglioni

et al. 2020

Preprint

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169/175) 20 21Cyclic AMP is produced in cells by two very different types of adenylyl cyclases: the canonical 22 transmembrane adenylyl cyclases (tmACs, ADCY1~9) and the evolutionarily more conserved soluble 23 adenylyl cyclase (sAC, ADCY10). While the role and regulation of tmACs is well documented, much 24 less is known of sAC in cellular metabolism. We demonstrate here that sAC is an acute regulator of 25 glycolysis, oxidative phosphorylation and glycogen metabolism, tuning their relative bioenergetic 26 contributions. Suppression of sAC activity leads to aerobic glycolysis, enhanced glycogenolysis, 27 decreased oxidative phosphorylation, and an elevated cytosolic NADH/NAD + ratio, resembling the 28 Warburg phenotype. Importantly, we found that glycogen metabolism is regulated in opposite 29 directions by cAMP depending on its location of synthesis and downstream effectors. While the 30 canonical tmAC-cAMP-PKA axis promotes glycogenolysis, we identify a novel sAC-cAMP-Epac1 axis 31 that suppresses glycogenolysis. These data suggest that sAC is an autonomous bioenergetic sensor 32 that suppresses aerobic glycolysis and glycogenolysis when ATP levels suffice. When the ATP level 33 falls, diminished sAC activity induces glycogenolysis and aerobic glycolysis to maintain energy 34 homeostasis.35 36 56 CO2 are the primary product of substrate oxidation by the TCA cycle, we hypothesized that sAC 57 regulates the autonomous metabolism of cells and this is supported by several characteristics of the 58 enzyme. Firstly, sAC can directly sense the cellular energetic state due to its high Km for its substrate 59 ATP (ranging from 1 to 10 mM) (Jaiswal & Conti, 2003, Litvin et al., 2003, Zippin, Chen et al., 2013. 60Secondly, albeit at low level, sAC is expressed in almost all tissues examined (Geng, Wang et al., 2005, 61 Levin & Buck, 2015). Thirdly, Ca 2+ , another versatile and universal second messenger, stimulates sAC 62 in synergy with bicarbonate (Geng et al., 2005, Jaiswal & Conti, 2003, allowing sAC to tune the 63 cellular metabolism according to ongoing cellular signaling. In line with this reasoning, the ATP-and 64 calcium-sensing properties of sAC have been demonstrated to facilitate diverse metabolic 65 regulations, including the regulation of oxidative phosphorylation by sensing CO2 production from 66 the TCA cycle (Acin-Perez, Salazar et al., 2009) and/or free Ca 2+ concentrations in the mitochondrial 67 matrix (Di Benedetto, Scalzotto et al., 2013), induction of ATP-dependent insulin secretion in the 68 pancreas (Zippin et al., 2013), secretion of aldosterone in adrenal cortex carcinoma H295R (Katona, 69 4 Rajki et al., 2015), and TNF-induced respiratory burst in human neutrophils (Han, Stessin et al., 2005). 71Over the past decade, it has become widely accepted that cAMP signaling is compartmentalized 72 into microdomains which allows this single messenger molecule to mediate disparate functions even 73 within a single cell. (Kamenetsky et al., 2006, Lefkimmiatis & Zaccolo, 2014. We have therefore 74 exa...

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Section: Resultssupporting

confidence: 91%

Section: Discussionmentioning

confidence: 90%

Non-canonical regulation of glycogenolysis and the Warburg phenotype by soluble adenylyl cyclase

Chang

Gilglioni

et al. 2020

Preprint

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“…We derived MEF cell lines from sAC KO mice and from their WT littermates ( Ramos-Espiritu et al, 2016 ). sAC KO 3T3 MEFs (hereafter referred to as sAC KO MEFs) generate less cAMP than WT MEFs, and unlike in WT MEFs, all the cAMP generated in sAC KO MEFs is insensitive to the sAC-specific inhibitor KH7 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Mouse embryonic fibroblasts (MEFs) were immortalized from WT and sAC KO mice ( Esposito et al, 2004 ; Hess et al, 2005 ) using the 3T3 method or SV40 large T antigen ( Ramos-Espiritu et al, 2016 ). The cells were grown in DMEM supplemented with 1% penicillin/streptomycin, 10% fetal bovine serum, and 0.5% glutamine, and they were genetically and functionally authenticated in our laboratory.…”

Section: Methodsmentioning

confidence: 99%

Soluble adenylyl cyclase is essential for proper lysosomal acidification

Rahman

Ramos‐Espiritu

Milner

et al. 2016

Journal of General Physiology

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“…There may be other sAC-defined cAMP compartments revealed by additional phenotypes in sAC KO MEFs. We have previously shown that sAC KO MEFs display a lysosomal acidification defect (Rahman et al, 2016) and are more susceptible to oncogenic transformation than wt cells (Ramos-Espiritu et al, 2016a). However, neither of these phenotypes has been ascribed to a specifically localized isoform of sAC, so it is unclear whether they define unique cAMP functional compartments.…”

Section: Discussionmentioning

confidence: 99%

Distinct intracellular sAC-cAMP domains regulate ER Ca2+ signaling and OXPHOS function

Valsecchi

Konràd

D'Aurelio

et al. 2017

Journal of Cell Science

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cAMP regulates a wide variety of physiological functions in mammals. This single second messenger can regulate multiple, seemingly disparate functions within independently regulated cell compartments. We have previously identified one such compartment inside the matrix of the mitochondria, where soluble adenylyl cyclase (sAC) regulates oxidative phosphorylation (OXPHOS). We now show that sAC knockout fibroblasts have a defect in OXPHOS activity and attempt to compensate for this defect by increasing OXPHOS proteins. Importantly, sAC knockout cells also exhibit decreased probability of endoplasmic reticulum (ER) Ca release associated with diminished phosphorylation of the inositol 3-phosphate receptor. Restoring sAC expression exclusively in the mitochondrial matrix rescues OXPHOS activity and reduces mitochondrial biogenesis, indicating that these phenotypes are regulated by intramitochondrial sAC. In contrast, Ca release from the ER is only rescued when sAC expression is restored throughout the cell. Thus, we show that functionally distinct, sAC-defined, intracellular cAMP signaling domains regulate metabolism and Ca signaling.

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The metabolic/pH sensor soluble adenylyl cyclase is a tumor suppressor protein

Cited by 19 publications

References 47 publications

Non-canonical regulation of glycogenolysis and the Warburg phenotype by soluble adenylyl cyclase

Non-canonical regulation of glycogenolysis and the Warburg phenotype by soluble adenylyl cyclase

Soluble adenylyl cyclase is essential for proper lysosomal acidification

Distinct intracellular sAC-cAMP domains regulate ER Ca2+ signaling and OXPHOS function

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