Mutant Ras Elevates Dependence on Serum Lipids and Creates a Synthetic Lethality for Rapamycin

Salloum, Darin; Mukhopadhyay, Suman; Tung, Kaity; Polonetskaya, Aleksandra; Foster, David A.

doi:10.1158/1535-7163.mct-13-0762

Cited by 25 publications

(36 citation statements)

References 25 publications

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“…19 We chose to investigate 2 K-Ras-driven cancer cells -MDA-MB-231 breast and Calu-1 lung cancer cells, which we have used previously to address the vulnerability of Ras-driven cancer cells that had entered S-phase. 19,20 We wanted to establish a G 1 or G 0 cell cycle arrest that was upstream from the late G1 site where rapamycin arrests cells. 10 Using serum withdrawal to arrest cancer cells in G 0 is problematic because most cancer cells have acquired a mutationsuch as Ras, which permits passage through the growth factor-dependent restriction point.…”

Section: Resultsmentioning

confidence: 99%

Apoptotic effects of high-dose rapamycin occur in S-phase of the cell cycle

et al. 2015

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Abbreviations: 4E-BP1, eIF4E binding protein-1; eIF4E, eukaryotic initiation factor 4E; Gln, glutamine; GOT, glutamateoxaloacetate-transaminase; mTOR, mammalian target of rapamycin; mTORC1/2, mTOR complex 1/2; PARP, poly-ADP-ribose polymerase; PI3K, phosphatidylinositol-3-kinase; S6K, S6 kinase; TGF-b, transforming growth factor-b.Mutations in genes encoding regulators of mTOR, the mammalian target of rapamycin, commonly provide survival signals in cancer cells. Rapamycin and analogs of rapamycin have been used with limited success in clinical trials to target mTOR-dependent survival signals in a variety of human cancers. Suppression of mTOR predominantly causes G1 cell cycle arrest, which likely contributes to the ineffectiveness of rapamycin-based therapeutic strategies. While rapamycin causes the accumulation of cells in G1, its effect in other cell cycle phases remains largely unexplored. We report here that when synchronized MDA-MB-231 breast cancer cells are allowed to progress into S-phase from G 1 , rapamycin activates the apoptotic machinery with a concomitant increase in cell death. In Calu-1 lung cancer cells, rapamycin induced a feedback increase in Akt phosphorylation at Ser473 in S-phase that mitigated rapamycin-induced apoptosis. However, sensitivity to rapamycin in S-phase could be reestablished if Akt phosphorylation was suppressed. We recently reported that glutamine (Gln) deprivation causes K-Ras mutant cancer cells to aberrantly arrest primarily in S-phase. Consistent with observed sensitivity of S-phase cells to rapamycin, interfering with Gln utilization sensitized both MDA-MB-231 and Calu-1 K-Ras mutant cancer cells to the apoptotic effect of rapamycin. Importantly, rapamycin induced substantially higher levels of cell death upon Gln depletion than that observed in cancer cells that were allowed to progress through S-phase after being synchronized in G 1 . We postulate that exploiting metabolic vulnerabilities in cancer cells such as S-phase arrest observed with K-Ras-driven cancer cells deprived of Gln, could be of great therapeutic potential.

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Section: Resultsmentioning

confidence: 99%

Apoptotic effects of high-dose rapamycin occur in S-phase of the cell cycle

et al. 2015

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“…More recently, we reported that PLD activity is also elevated in response to changing from medium with 10% serum to 10% delipidated serum (48). The effect appears to be a stress response in Ras-driven cancer cells because these cells have a greater need for exogenously supplied lipids (48,49). Rasdriven cancer cells have a compromised ability to increase levels of stearoyl-CoA desaturase-1 in response to serum withdrawal (48).…”

Section: Compensatory Production Of Pa In Response To Metabolic Stresmentioning

confidence: 95%

“…The effect appears to be a stress response in Ras-driven cancer cells because these cells have a greater need for exogenously supplied lipids (48,49). Rasdriven cancer cells have a compromised ability to increase levels of stearoyl-CoA desaturase-1 in response to serum withdrawal (48). Thus, newly synthesized fatty acids cannot be desaturated, which is essential for synthesis of phospholipids targeted for membranes.…”

Section: Compensatory Production Of Pa In Response To Metabolic Stresmentioning

confidence: 99%

Phospholipase D and the Maintenance of Phosphatidic Acid Levels for Regulation of Mammalian Target of Rapamycin (mTOR)

Foster

Salloum

Menon

et al. 2014

Journal of Biological Chemistry

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107

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Phosphatidic acid (PA) is a critical metabolite at the heart of membrane phospholipid biosynthesis. However, PA also serves as a critical lipid second messenger that regulates several proteins implicated in the control of cell cycle progression and cell growth. Three major metabolic pathways generate PA: phospholipase D (PLD), diacylglycerol kinase (DGK), and lysophosphatidic acid acyltransferase (LPAAT). The LPAAT pathway is integral to de novo membrane phospholipid biosynthesis, whereas the PLD and DGK pathways are activated in response to growth factors and stress. The PLD pathway is also responsive to nutrients. A key target for the lipid second messenger function of PA is mTOR, the mammalian/mechanistic target of rapamycin, which integrates both nutrient and growth factor signals to control cell growth and proliferation. Although PLD has been widely implicated in the generation of PA needed for mTOR activation, it is becoming clear that PA generated via the LPAAT and DGK pathways is also involved in the regulation of mTOR. In this minireview, we highlight the coordinated maintenance of intracellular PA levels that regulate mTOR signals stimulated by growth factors and nutrients, including amino acids, lipids, glucose, and Gln. Emerging evidence indicates compensatory increases in one source of PA when another source is compromised, highlighting the importance of being able to adapt to stressful conditions that interfere with PA production. The regulation of PA levels has important implications for cancer cells that depend on PA and mTOR activity for survival.

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“…The paraffin-embedded sections were stained with antibodies against K-ras antibody as previously reported (Salloum et al, 2014). Tissue array slides were deparaffinized 3 times with Xylene, each for 5 min.…”

Section: Immunohistochemistrymentioning

confidence: 99%