Synthetic lethal metabolic targeting of cellular senescence in cancer therapy

Dörr, Jan R.; Yu, Yong A.; Milanovic, Maja; Beuster, Gregor; Zasada, Christin; Däbritz, J. Henry M.; Lisec, Jan; Lenze, Dido; Gerhardt, Anne; Schleicher, Katharina; Kratzat, Susanne; Purfürst, Bettina; Walenta, Stefan; Mueller‐Klieser, Wolfgang; Gräler, Markus H.; Hummel, Michael; Keller, Ulrich; Buck, Andreas K.; Dörken, Bernd; Willmitzer, Lothar; Reimann, Maurice; Kempa, Stefan; Lee, Soyoung; Schmitt, Clemens A.

doi:10.1038/nature12437

Cited by 449 publications

(442 citation statements)

References 44 publications

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“…In this setting autophagy mitigates ER stress caused by BRAF V600E inhibition, highlighting the additional importance of therapy-induced autophagy as a resistance mechanism (46). Indeed, there are other examples of therapy-induced autophagy functioning as a resistance mechanism, suggesting that augmentation of the anticancer activity of autophagy inhibitor therapeutics may be generally applicable (47)(48)(49)(50).…”

Section: Acknowledgmentsmentioning

confidence: 99%

The role for autophagy in cancer

White¹

2015

J. Clin. Invest.

1,067

919

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Autophagy is a tissue-specific regulator of homeostasis and survivalAutophagy captures and degrades intracellular components such as proteins and organelles to sustain metabolism and homeostasis. Low levels of basal autophagy prevent the gradual accumulation of damaged proteins and organelles in tissues that is toxic over time; thus, autophagy plays an important role in protein and organelle quality control (1). Identification of the autophagy substrates that are deregulated in autophagy-deficient cells and tissues is important to understand the biological role and tissue specificity of autophagy. Determination of the global impact of autophagy on the cellular proteome would be a significant advance, as we are only beginning to understand the broad scope of autophagy substrates and the functional consequence of deregulating their degradation and recycling.Some tissues such as liver, brain, and muscle are particularly dependent on autophagy to prevent the buildup of damaged mitochondria and protein aggregates containing the autophagy substrate p62/SQSTM1 (p62) and ubiquitin (1). Accumulation of defective mitochondria that results from impaired autophagy can perturb metabolism and generate oxidative stress (2). Autophagy also mitigates ER stress, and autophagy defects can produce accumulation of chaperone proteins that increase the unfolded protein burden (3, 4). Select protein elimination by autophagy is also important for homeostasis. The toxicity of autophagy defects in liver is partly ameliorated by deficiency in the autophagy substrate p62, but this is not the case for the brain (5, 6). The recent revelation that autophagy is important for recycling iron complexed with ferritin through ferritinophagy may be critical for iron homeostasis in many tissues, potentially including brain (7).The accumulation of, or imbalance in, levels of some cellular components caused by autophagy defects may be indirect. For example, lipid accumulation in autophagy-deficient liver and some lung tumors can arise from defects in the autophagy of lipid droplets through lipophagy (8) or indirectly from defects in mitochondrial fatty acid oxidation (FAO) that repress lipid catabolism (9). These findings collectively demonstrate the broad effects of autophagy on cellular homeostasis at the level of substrate removal, maintenance of organelle function, and detoxification. Thus, autophagy dependence is tissue specific, not only for the general requirement for the level of autophagic activity, but also for the nature of the substrates that require autophagy-mediated elimination or recycling.Acute autophagy induction is critical for yeast and normal mammalian cells and mammals to survive starvation, which is attributed to the recycling of intracellular components into metabolic pathways (2). Autophagy thereby functions to promote metabolic homeostasis and survival that is essential during nutrient deprivation. While it is generally appreciated that autophagy-mediated degradation of intracellular proteins and organelles provides metabolic s...

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Section: Acknowledgmentsmentioning

confidence: 99%

The role for autophagy in cancer

White¹

2015

J. Clin. Invest.

1,067

919

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“…Senes cence is po ten tially harm ful be cause of its pe cu liar se cre tory pro file known as the senes cence as so ci ated se cre tory phe no type (SASP), which has been iden ti fied to drive tu mor in flam ma tion and pro gres sion [138]. Senes cent can cer cells have a hy per me ta bolic phe no type char ac ter ized by ac cel er ated gly col y sis and mi to chon dr ial oxy gen con sump tion [139]. This meta bolic re pro gram ming is re quired to cope with SASP as it is a highly en ergy de mand ing process.…”

Section: Metabolic Regulation Of Cancer Cell Deathmentioning

confidence: 99%

Cancer metabolism in space and time: Beyond the Warburg effect

Danhier

Bański

Payen

et al. 2017

Biochimica et Biophysica Acta (BBA) - Bioenergetics

161

134

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Available online xxx Keywords:Can cer Me tab o lism Mi to chon dria Het ero gene ity Metas ta sis A B S T R A C T Al tered me tab o lism in can cer cells is piv otal for tu mor growth, most no tably by pro vid ing en ergy, re duc ing equiv a lents and build ing blocks while sev eral metabo lites ex ert a sig nal ing func tion pro mot ing tu mor growth and pro gres sion. A can cer tis sue can not be sim ply re duced to a bulk of pro lif er at ing cells. Tu mors are in deed com plex and dy namic struc tures where sin gle cells can het ero ge neously per form var i ous bi o log i cal ac tiv i ties with dif fer ent meta bolic re quire ments. Be cause tu mors are com posed of dif fer ent types of cells with meta bolic ac tiv i ties af fected by dif fer ent spa tial and tem po ral con texts, it is im por tant to ad dress me tab o lism tak ing into ac count cel lu lar and bi o log i cal het ero gene ity. In this re view, we de scribe this het ero gene ity also in meta bolic fluxes, thus show ing the rel a tive con tri bu tion of dif fer ent meta bolic ac tiv i ties to tu mor pro gres sion ac cord ing to the cel lu lar con text. This ar ti cle is part of a Spe cial Is sue en ti tled Res pi ra tory com plex I, edited by Giuseppe Gas parre, Ro drigue Rossig nol and Pierre Son veaux. Abbreviations: ACL, ATP cit rate lyase; AMPK, adeno sine monophos phate ki nase; ARG1, L argi nine me tab o liz ing en zyme arginase 1; BCAA, branched chain amino acid; Bcl2, B cell lym phoma 2; CAF, can cer as so ci ated fi brob last; CIC, can cer ini ti at ing cell; COX2, cy tochrome ox i dase; CSC, can cer stem cell; CREB, cyclic adeno sine monophos phate re sponse el e ment bind ing pro tein; DEC1, dif fer en tially ex pressed in chon dro cytes 1; EMT, ep ithe lial to mes enchy mal tran si tion; FAK, fo cal ad he sion ki nase; FAS, fatty acid syn thase; FBP, fruc tose 1,6 bis pho s phate; FDG PET, [ F] flu o rodeoxyglu cose positron emis sion to mog ra phy; GAPDH, glyc er alde hyde 3 phos phate de hy dro ge nase; HIF 1, hy poxia ac ti vated fac tor 1; HK2, hex ok i nase 2; HMGB1, high mo bil ity group box 1; HU VEC, hu man um bil i cal vein en dothe lial cell; IFN γ, in ter feron gamma; LDH, lac tate de hy dro ge nase; MEF, murine em bry onic fi brob last; MET, mes enchy mal to ep ithe lial tran si tion; MRI, mag netic res o nance imag ing; mTORC1, mam malian tar get of ra pamycin com plex 1; NSCLC, non small cell lung can cer; OX PHOS, ox ida tive phos pho ry la tion; PDAC, pan cre atic duc tal ade no car ci noma; PHD, pro lyl hy drox y lase; pHe, ex tra cel lu lar pH; pHi, in tra cel lu lar pH; PK, pyru vate ki nase; PPP, pen tose phos phate path way; REDD1, reg u lated in de vel op ment and DNA dam age re sponse 1; RhoA, Ras ho molog gene fam ily, mem ber A; ROS, re ac tive oxy gen species; SASP, senes cence as so ci ated se cre tory phe no type; SCO2, syn the sis of cy tochrome ox i dase 2; SGK 1, serum and glu co cor ti coid reg u lated ki nase 1 Sirt1, sir tuin 1; TAM, tu mor as so ci ated macrophage; TIGAR, TP53 in duced gly col y ...

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“…The inhibition of SL proteins has been successfully applied in the field of cancer therapeutics [100,101], and has been investigated as a means to discover new antibiotic combination partners. SL combines the advantages of multitargeting with the inability of an organism to overcome pressure on essential biochemical activities.…”

Section: Synthetic Lethality Inferencementioning

confidence: 99%

Resisting resistance: is there a solution for malaria?

Verlinden

Louw

Birkholtz

2016

Expert Opinion on Drug Discovery

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IntroductionCurrently, widely used antimalarial drugs have a limited clinical lifespan due to parasite resistance development. With resistance continuously rising, antimalarial drug discovery requires strategies to decrease the time of delivering a new antimalarial drug while simultaneously increasing the drug"s therapeutic lifespan. Areas coveredLessons learnt from various chemotherapeutic resistance studies in the fields of antibiotic and cancer research offer potentially useful strategies that can be applied to antimalarial drug discovery. In this review we discuss current strategies to circumvent resistance in malaria and alternatives that could be employed. Expert opinionWe have been "beating back" the malaria parasite with novel drugs for the past 49 years but the constant rise in antimalarial drug resistance is forcing the drug discovery community to explore alternative strategies. Avant-garde anti-resistance strategies from alternative fields may assist our endeavors to manage, control and prevent antimalarial drug resistance to progress beyond beating the resistant parasite back, to stopping it dead in its tracks. Here we investigate the 2 development of strategies that are able to either overwhelm or outwit the parasite in its attempts to develop resistance. Article Highlights box In most instances the malaria parasite develops drug resistance at a faster rate than a novel antimalarial drug can be developed. For antimalarial drug discovery to remain sustainable, the clinical lifespan of an antimalarial drug must as least exceed the time taken to develop the drug. Currently, antimalarial drug resistance is being controlled through the development of novel drugs, which are combined with an appropriate drug partner into a combination therapy. Polypharmacology (multitargeting) may be able to speed up the delivery of a novel antimalarial drug while simultaneously increasing the clinical lifespan of the drug. Unexplored targets such as the virulence potential, hijacked host factors and stress factors may deliver drugs that can effectively resist resistance. Other post-resistance strategies such as molecular decoys and chemogenomics may also prove valuable in curbing resistance.

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Synthetic lethal metabolic targeting of cellular senescence in cancer therapy

Cited by 449 publications

References 44 publications

The role for autophagy in cancer

The role for autophagy in cancer

Cancer metabolism in space and time: Beyond the Warburg effect

Resisting resistance: is there a solution for malaria?

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