Oncogenic KRAS signaling activates mTORC1 through COUP‐TFII‐mediated lactate production

Byun, Jun‐Kyu; Park, Mihyang; Yun, Jae Won; Lee, Jaebon; Kim, Jae Sun; Cho, Sung Jin; Lee, You Mie; Lee, Inkyu; Choi, Youn‐Hee; Park, Keun Gyu

doi:10.15252/embr.201847451

Cited by 30 publications

(23 citation statements)

References 37 publications

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“…Riemann et al 33 reported that extracellular acidosis results in a rapid, sustained decrease in intracellular pH (pH i ) and tissue hypoxia, and induces increased transcription factor phosphorylation and tumor cells transcriptional activity 33 . The involvement of lactic acid in cancer has attracted attention only recently, and lactic acid directly contributes to tumor growth and progression (i.e., the lactate anion and protons) as an oxidative fuel and support for angiogenesis and metastasis 34,35 . For example, extracellular lactic acid acidosis causes a lower pH i and higher intracellular lactate concentration, and rescues 4T1 (murine breast cancer) cells from glucose deprivation 36 .…”

Section: Discussionmentioning

confidence: 99%

Long-term high-grain diet alters ruminal pH, fermentation, and epithelial transcriptomes, leading to restored mitochondrial oxidative phosphorylation in Japanese Black cattle

Ogata

Makino

Ishizuka

et al. 2020

Sci Rep

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to increase intramuscular fat accumulation, Japanese Black beef cattle are commonly fed a high-grain diet from 10 to 30 months of age. Castrated and fistulated cattle (n = 9) were fed a high-concentrate diets during the early, middle, and late stages consecutively (10-14, 15-22, 23-30 months of age, respectively). Ruminal pH was measured continuously, and rumen epithelium and fluid samples were collected on each stage. The 24-h mean ruminal pH during the late stage was significantly lower than that during the early stage. Total volatile fatty acid (VFA) and lactic acid levels during the late stage were significantly lower and higher, respectively, than those during the early and middle stages. In silico analysis of differentially expressed genes showed that "Oxidative Phosphorylation" was the pathway inhibited most between the middle and early stages in tandem with an inhibited upstream regulator (PPARGC1A, also called PGC-1α) but the most activated pathway between the late and middle stages. these results suggest that mitochondrial dysfunction and thereby impaired cell viability due to acidic irritation under the higher VFA concentration restored stable mitochondrial oxidative phosphorylation and cell viability by higher lactic acid levels used as cellular oxidative fuel under a different underlying mechanism in subacute ruminal acidosis. A high-grain diet promotes the growth, productivity, and quality of meat or milk production in beef and dairy cattle. On a high-grain diet, organic acids such as volatile fatty acids (VFAs) and lactic acid accumulate in the rumen 1,2. Ruminal pH is critical in the maintenance of normal, stable fermentation, microbial populations, and absorptive function 2-4 , and is determined by the balance between acid production by microbes and acid removal by absorption, neutralization, and clearance 1,5,6 , in a host-microbiome interaction 7. The occurrence of subacute ruminal acidosis (SARA) defined by a rumen pH <5.6 is due to the non-physiological accumulation of VFAs, while ruminal acidosis defined by a rumen pH <5.0 is associated with accumulated lactic acid in the rumen 2. Several short-(days) or mid-term (weeks) studies have shown that SARA or rumen acidosis challenges affected the rumen epithelial structure, gene expression, and transcriptomes 8-10. For example, in one study, 3 weeks of a high-grain diet (65% grain) compromised the structural integrity and led to the appearance of undifferentiated cells near the stratum corneum of the rumen papillae in non-lactating dairy cattle 8. In another, the rumen papillae in dairy cattle fed a total mixed ration had increased epithelial desquamation and sloughing scores during early lactation, as well as upregulation of genes encoding desmosome assembly (despoglein1 and corneodesmosin), epidermal growth factor (EGF) signaling (epiregulin), transforming growth factor β (TGFB)

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Section: Discussionmentioning

confidence: 99%

Long-term high-grain diet alters ruminal pH, fermentation, and epithelial transcriptomes, leading to restored mitochondrial oxidative phosphorylation in Japanese Black cattle

Ogata

Makino

Ishizuka

et al. 2020

Sci Rep

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“…Previous studies have already shown that the siRNA knockdown of ERα in MCF-7 breast cancer cells decreased COUP-TFII expression while treatment with estradiol increased the expression of COUP-TFII, revealing a positive correlation between COUP-TFII and ERα status (104). A recent study also reported another mechanism of how COUF-TFII might influence LAM pathogenesis, in which lactate production induced by upregulated COUP-TFII in KRAS-activated cells increases mTORC1 activity by disrupting the interaction of TSC2 and Rheb (105) (Figure 1). Thus, NR2F2 could be a promising candidate to explain the gene origin of S-LAM and pathogenesis of LAM.…”

Section: Nr2f2 Located By Gwas In S-lam Patientsmentioning

confidence: 91%

Possible Novel Therapeutic Targets in Lymphangioleiomyomatosis Treatment

et al. 2020

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Lymphangioleiomyomatosis (LAM) is a rare systemic neoplastic disease that exclusively happens in women. Studies focusing on LAM and tuberous sclerosis complex (TSC) have made great progress in understanding the pathogenesis and searching for treatment. The inactive mutation of TSC1 or TSC2 is found in patients with LAM to activate the crucial mammalian target of rapamycin (mTOR) signaling pathway and result in enhanced cell proliferation and migration. However, it does not explain every step of tumorigenesis in LAM. Because cessation of rapamycin would break the stabilization of lung function or improved quality of life and lead to disease recurrent, continued studies on the pathogenesis of LAM are necessary to identify novel targets and new treatment. Researchers have found several aberrant regulations that affect the mTOR pathway such as its upstream or downstream molecules and compensatory pathways in LAM. Some therapeutic targets have been under study in clinical trials. New methods like genome-wide association studies have located a novel gene related to LAM. Herein, we review the current knowledge regarding pathogenesis and treatment of LAM and summarize novel targets of therapeutic potential recently.

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“…Besides serving as a nutrient, lactate may play a role in SSC maturation. Similarly to cancer cells, in which lactate was shown to enhance mTOR activity [ 215 ], it also contributes to the activation of AKT [ 216 ], inhibits apoptosis [ 217 ], and enhances transcription and translation through-put [ 218 ] in male germ cells.…”

Section: Metabolic Regulation Within the Testismentioning

confidence: 99%

Metabolic Requirements for Spermatogonial Stem Cell Establishment and Maintenance In Vivo and In Vitro

Voigt

Thiageswaran

Lara

et al. 2021

IJMS

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The spermatogonial stem cell (SSC) is a unique adult stem cell that requires tight physiological regulation during development and adulthood. As the foundation of spermatogenesis, SSCs are a potential tool for the treatment of infertility. Understanding the factors that are necessary for lifelong maintenance of a SSC pool in vivo is essential for successful in vitro expansion and safe downstream clinical usage. This review focused on the current knowledge of prepubertal testicular development and germ cell metabolism in different species, and implications for translational medicine. The significance of metabolism for cell biology, stem cell integrity, and fate decisions is discussed in general and in the context of SSC in vivo maintenance, differentiation, and in vitro expansion.

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Oncogenic KRAS signaling activates mTORC1 through COUP‐TFII‐mediated lactate production

Cited by 30 publications

References 37 publications

Long-term high-grain diet alters ruminal pH, fermentation, and epithelial transcriptomes, leading to restored mitochondrial oxidative phosphorylation in Japanese Black cattle

Long-term high-grain diet alters ruminal pH, fermentation, and epithelial transcriptomes, leading to restored mitochondrial oxidative phosphorylation in Japanese Black cattle

Possible Novel Therapeutic Targets in Lymphangioleiomyomatosis Treatment

Metabolic Requirements for Spermatogonial Stem Cell Establishment and Maintenance In Vivo and In Vitro

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