Phosphoinositide 3-Kinase Regulates Glycolysis through Mobilization of Aldolase from the Actin Cytoskeleton

Hu, Hai; Juvekar, Ashish; Lyssiotis, Costas A.; Lien, Evan C.; Albeck, John G.; Oh, Doogie; Varma, Gopal; Hung, Yin P.; Ullas, Soumya; Lauring, Josh; Seth, Pankaj; Lundquist, Mark R.; Tolan, Dean R.; Grant, Aaron K.; Needleman, Daniel; Asara, John M.; Cantley, Lewis C.; Wulf, Gerburg M.

doi:10.1016/j.cell.2015.12.042

Cited by 318 publications

(230 citation statements)

References 38 publications

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“…As shown in Fig. 3A and reported earlier (15), glycolysis was only modestly reduced by AKT inhibitor MK2206 (Fig. 3A), whereas PI3K inhibitor BKM120 lowered the glycolytic rate strongly, particularly after mobilization of the glycolytic reserve with oligomycin (Fig.…”

Section: Pi3k Inhibition Causes a Selective Decrease In Nonoxidative mentioning

confidence: 60%

“…We have recently shown that PI3K directly coordinates glycolysis with cytoskeletal dynamics: PI3K-dependent activation of the GTPase Rac leads to an increased turnover of the actin cytoskeleton with release of the F-actin-bound glycolytic enzyme aldolase A into the cytoplasm where it is enzymatically active. Consistently, inhibitors of PI3K, but not inhibitors of the protein kinase AKT, SGK (serum/ glucocorticoid regulated kinase), or mechanistic target of rapamycin (mTOR), cause a significant decrease in glycolysis at the step catalyzed by aldolase A, whereas activating PIK3CA mutations have the opposite effect (15). A product of the aldolase reaction is the triose glyceraldehyde 3-phosphate (Ga3P), which is a substrate for transketolase (TKT).…”

mentioning

confidence: 95%

“…We recently found that activation of PI3K, and not AKT, enhances glycolytic flux at the step of aldolase (15). The reverse aldol condensation catalyzed by aldolase generates Ga3P, which is the triose acted on by TKT, the first step in the nonoxidative PPP that produces R5P required for base ribosylation.…”

Section: The Antitumor Efficacy Of the Pi3k And Parp Inhibitor Combinmentioning

confidence: 99%

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Phosphoinositide 3-kinase inhibitors induce DNA damage through nucleoside depletion

Juvekar

Yadegarynia

et al. 2016

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

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We previously reported that combining a phosphoinositide 3-kinase (PI3K) inhibitor with a poly-ADP Rib polymerase (PARP)-inhibitor enhanced DNA damage and cell death in breast cancers that have genetic aberrations in BRCA1 and TP53. Here, we show that enhanced DNA damage induced by PI3K inhibitors in this mutational background is a consequence of impaired production of nucleotides needed for DNA synthesis and DNA repair. Inhibition of PI3K causes a reduction in all four nucleotide triphosphates, whereas inhibition of the protein kinase AKT is less effective than inhibition of PI3K in suppressing nucleotide synthesis and inducing DNA damage. Carbon flux studies reveal that PI3K inhibition disproportionately affects the nonoxidative pentose phosphate pathway that delivers Rib-5-phosphate required for base ribosylation. In vivo in a mouse model of BRCA1-linked triple-negative breast cancer (K14-Cre BRCA1), the PI3K inhibitor BKM120 led to a precipitous drop in DNA synthesis within 8 h of drug treatment, whereas DNA synthesis in normal tissues was less affected. In this mouse model, combined PI3K and PARP inhibition was superior to either agent alone to induce durable remissions of established tumors. T riple-negative breast cancers, including BRCA1-linked breast cancers, frequently show activation of the PI3K pathway as a result of overexpression of epidermal growth factor receptor (EGFR) (1, 2) or insulin-like growth factor 1 receptor (IGFR) (3), and inhibition of the EGFR (1, 2, 4) and/or the PI3K/Nrf2 axis (5) prevents cancers arising from BRCA1 mutant mammary epithelial cells (MECs). In addition, activating mutations of PIK3CA, or loss of the inhibitory lipid phosphatases PTEN (phosphatase and tensin homolog) and INPP4B (inositol polyphosphate 4-phosphatase type II) (6, 7), suggest that the PI3K pathway is contributing to tumor growth and survival. Aside from their role in regulating the homeostasis of phospho-inositides, PTEN and INPP4B may have independent roles in DNA damage repair. A role for PTEN in the maintenance of genomic stability was identified (8); more recently, INPP4B was found to directly interact with BRCA1 and the serine/threonine protein kinase ATR, and its loss destabilizes these DNA damage repair complexes, effectively sensitizing INPP4B-deficient cells to poly-ADP Rib polymerase (PARP) inhibition (9).Despite the high incidence of predisposing lesions in the PI3K pathway, limited clinical activity has been observed with PI3K inhibitors as single-agent treatment in endocrine-resistant breast cancer, which may reflect bypass of PI3K-dependent mitogenic signaling by alternative signaling pathways such as the MAPK pathway. Therefore, concurrent inhibition of parallel and compensatory signaling networks to overcome resistance to PI3K inhibition is being investigated in clinical studies. This approach, however, carries the risk of overlapping toxicities of the targeted agents without sufficient efficacy because tumor cells may have greater plasticity for redundant signaling than normal tissues.Mul...

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Section: Pi3k Inhibition Causes a Selective Decrease In Nonoxidative mentioning

confidence: 60%

mentioning

confidence: 95%

Section: The Antitumor Efficacy Of the Pi3k And Parp Inhibitor Combinmentioning

confidence: 99%

See 1 more Smart Citation

Phosphoinositide 3-kinase inhibitors induce DNA damage through nucleoside depletion

Juvekar

Yadegarynia

et al. 2016

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

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“…In addition, it should be noted that the enzymatic assay disrupts cellular structure and therefore does not detect the regulation of enzymatic activity according to cellular localization. This is important because some glycolytic enzymes, including Aldoa, are localized to specific cellular compartments in addition to the cytoplasm (Hu et al, 2016;Mamczur et al, 2013), and therefore regulation of the cellular localization of glycolytic enzymes could be one of the mechanisms that regulate glucose metabolism rewiring during CB. Area values were normalized to the amount of protein extracted from the embryos, and the relative ratios to E8.5 embryos are shown.…”

Section: Discussionmentioning

confidence: 99%

Rewiring of embryonic glucose metabolism via suppression of PFK-1 and aldolase during mouse chorioallantoic branching

Miyazawa¹,

Yamaguchi²,

Honda³

et al. 2017

Journal of Cell Science

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Adapting the energy metabolism state to changing bioenergetic demands is essential for mammalian development accompanying massive cell proliferation and cell differentiation. However, it remains unclear how developing embryos meet the changing bioenergetic demands during the chorioallantoic branching (CB) stage, when the maternal-fetal exchange of gases and nutrients is promoted. In this study, using metabolome analysis with mass-labeled glucose, we found that developing embryos redirected glucose carbon flow into the pentose phosphate pathway via suppression of the key glycolytic enzymes PFK-1 and aldolase during CB. Concomitantly, embryos exhibited an increase in lactate pool size and in the fractional contribution of glycolysis to lactate biosynthesis. Imaging mass spectrometry visualized lactate-rich tissues, such as the dorsal or posterior neural tube, somites and head mesenchyme. Furthermore, we found that the heterochronic gene Lin28a could act as a regulator of the metabolic changes observed during CB. Perturbation of glucose metabolism rewiring by suppressing Lin28a downregulation resulted in perinatal lethality. Thus, our work demonstrates that developing embryos rewire glucose metabolism following CB for normal development.

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“…Specifically, oncogenic PI3Kα is thought to promote glycolysis by enabling heightened glucose uptake through regulation of GLUT1/4 protein translation (7) and subsequent plasma membrane translocation (8), as well as regulating metabolite pathways (9,10). However, enhanced glycolysis is also observed in rapidly proliferating cells, which requires increased glucose uptake (11).…”

mentioning

confidence: 99%

PIK3CA mutant tumors depend on oxoglutarate dehydrogenase

Ilić

Birsoy

Aguirre

et al. 2017

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

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Oncogenic PIK3CA mutations are found in a significant fraction of human cancers, but therapeutic inhibition of PI3K has only shown limited success in clinical trials. To understand how mutant PIK3CA contributes to cancer cell proliferation, we used genome scale lossof-function screening in a large number of genomically annotated cancer cell lines. As expected, we found that PIK3CA mutant cancer cells require PIK3CA but also require the expression of the TCA cycle enzyme 2-oxoglutarate dehydrogenase (OGDH). To understand the relationship between oncogenic PIK3CA and OGDH function, we interrogated metabolic requirements and found an increased reliance on glucose metabolism to sustain PIK3CA mutant cell proliferation. Functional metabolic studies revealed that OGDH suppression increased levels of the metabolite 2-oxoglutarate (2OG). We found that this increase in 2OG levels, either by OGDH suppression or exogenous 2OG treatment, resulted in aspartate depletion that was specifically manifested as auxotrophy within PIK3CA mutant cells. Reduced levels of aspartate deregulated the malate-aspartate shuttle, which is important for cytoplasmic NAD + regeneration that sustains rapid glucose breakdown through glycolysis. Consequently, because PIK3CA mutant cells exhibit a profound reliance on glucose metabolism, malate-aspartate shuttle deregulation leads to a specific proliferative block due to the inability to maintain NAD + /NADH homeostasis. Together these observations define a precise metabolic vulnerability imposed by a recurrently mutated oncogene.

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Phosphoinositide 3-Kinase Regulates Glycolysis through Mobilization of Aldolase from the Actin Cytoskeleton

Cited by 318 publications

References 38 publications

Phosphoinositide 3-kinase inhibitors induce DNA damage through nucleoside depletion

Phosphoinositide 3-kinase inhibitors induce DNA damage through nucleoside depletion

Rewiring of embryonic glucose metabolism via suppression of PFK-1 and aldolase during mouse chorioallantoic branching

PIK3CA mutant tumors depend on oxoglutarate dehydrogenase

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