The p53 tumor suppressor network in cancer and the therapeutic modulation of cell death

Chari, Nikhil; Pinaire, Nicole L.; Thorpe, Lynnelle; Medeiros, L. Jeffrey; Routbort, Mark J.; McDonnell, Timothy J.

doi:10.1007/s10495-009-0327-9

Cited by 50 publications

(55 citation statements)

References 164 publications

(212 reference statements)

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“…The intrinsic pathway is usually triggered in response to internal insults such as from oxidative stress, direct DNA damage, oncogenes, hypoxia, and depletion of survival factors [31][32]. Activation of the intrinsic pathway usually occurs through the stabilization and activation of p53, a well known regulator of cell growth arrest and apoptosis [31][32].…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…Activation of the intrinsic pathway usually occurs through the stabilization and activation of p53, a well known regulator of cell growth arrest and apoptosis [31][32]. This activation leads to transcriptional activation of pro-apoptotic proteins such as Bax and BID as well as modulators of apoptosis, Puma/ Noxa [31]. Bax, BID, and BIM can either be involved in formation of pore formation in the mitochondrial membrane leading to release of cytochrome c and other apoptogenic factors as in the extrinsic pathway and also be involved in antagonizing anti-apoptotic proteins, BCl- 2 BCL-XL, and BFL1 [31].…”

Section: Discussionmentioning

confidence: 99%

“…This activation leads to transcriptional activation of pro-apoptotic proteins such as Bax and BID as well as modulators of apoptosis, Puma/ Noxa [31]. Bax, BID, and BIM can either be involved in formation of pore formation in the mitochondrial membrane leading to release of cytochrome c and other apoptogenic factors as in the extrinsic pathway and also be involved in antagonizing anti-apoptotic proteins, BCl- 2 BCL-XL, and BFL1 [31]. Subsequent activation of caspase 9 and down-stream effectors such as caspase 3 and 7 lead to the same cell fate as in the extrinsic pathway.…”

Section: Discussionmentioning

confidence: 99%

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NSP 5a3a: A Potential Novel Cancer Target in Head and Neck Carcinoma

D’Agostino

Giordano

2010

Oncotarget

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AbstrAct:NSP 5a3a along with three other distinct though similar splice variants were initially identified corresponding to locus HCMOGT-1 on chromosome 17p11. Subsequent investigation, elucidated NSP 5a3a's potential involvement in cellular processes such as ribosome biogenesis and rRNA processing by validating NSP 5a3a's novel interaction with B23 and ribonuclear protein hnRNP-L possibly implicating NSP 5a3a's involvement in cellular activities such as RNA metabolism and processing [4]. In this preliminary investigation, we wanted to observe the effect that over-expressing NSP 5a3a may have on cell cycle and its potential application in cancer treatment in aggressive cancers such as head and neck carcinomas. Over-expressed NSP 5a3a in HN30 cells induced a significant degree of apoptosis, an average of a 10.85 fold increase compared to controls 3 days post-transfection. This effect was more significant then the apoptosis observed between Fadu cells over-expressing NSP 5a3a and its controls. Though, the apoptosis induced in the WI38 control cell line showed an average of a 13.2 fold increase between treated and controls comparable to the HN30 cell line 3 days post-transfection. Molecular analysis indentified a novel p73 dependent mechanism independent of p53 and caspase 3 activity through which NSP 5a3a is inducing apoptosis. We propose NSP 5a3a as a potential therapeutic target for site directed cancer treatment in perhaps certain head and neck carcinomas by induction of apoptosis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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NSP 5a3a: A Potential Novel Cancer Target in Head and Neck Carcinoma

D’Agostino

Giordano

2010

Oncotarget

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“…p53 activity is lost during the progression of many cancers, probably reflecting the fact that such a loss promotes genetic lability and cell proliferation, while blunting the apoptotic response to cytotoxic agents (Chari et al 2009;Athar et al 2011). In this regard, it is notable that AMPK can confer an activating phosphorylation to p53 at Ser15 (in humans), the same site targeted by the activating kinase ATM; (Jones et al 2005) this can help to fulfill AMPK's energy conservation mission by slowing cell cycle progression.…”

Section: Preventing and Controlling Cancermentioning

confidence: 99%

AMPK activation—protean potential for boosting healthspan

McCarty

2013

AGE

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AMP-activated kinase (AMPK) is activated when the cellular (AMP+ADP)/ATP ratio rises; it therefore serves as a detector of cellular "fuel deficiency." AMPK activation is suspected to mediate some of the health-protective effects of long-term calorie restriction. Several drugs and nutraceuticals which slightly and safely impede the efficiency of mitochondrial ATP g e n e r a t i o n -m o s t n o t a b l y m e t f o r m i n a n d berberine-can be employed as clinical AMPK activators and, hence, may have potential as calorie restriction mimetics for extending healthspan. Indeed, current evidence indicates that AMPK activators may reduce risk for atherosclerosis, heart attack, and stroke; help to prevent ventricular hypertrophy and manage congestive failure; ameliorate metabolic syndrome, reduce risk for type 2 diabetes, and aid glycemic control in diabetics; reduce risk for weight gain; decrease risk for a number of common cancers while improving prognosis in cancer therapy; decrease risk for dementia and possibly other neurodegenerative disorders; help to preserve the proper structure of bone and cartilage; and possibly aid in the prevention and control of autoimmunity. While metformin and berberine appear to have the greatest utility as clinical AMPK activators-as reflected by their efficacy in diabetes management-regular ingestion of vinegar, as well as moderate alcohol consumption, may also achieve a modest degree of healthprotective AMPK activation. The activation of AMPK achievable with any of these measures may be potentiated by clinical doses of the drug salicylate, which can bind to AMPK and activate it allosterically.

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The p53‐, Bax‐ and p21‐dependent inhibition of colon cancer cell growth by 5‐hydroxy polymethoxyflavones

Qiu

Guan

Dong

et al. 2010

Molecular Nutrition Food Res

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Previously, we reported that 5 hydroxy polymethoxyflavones (5OH-PMFs) isolated from orange, namely 5-hydroxy-6,7,8,3′,4′-pentamethoxyflavone (5HPMF), 5-hydroxy-3,6,7,8,3′,4′-hexamethoxyflavone (5HHMF), and 5-hydroxy-6,7,8,4´-tetramethoxyflavone (5HTMF) potently induced apoptosis and cell cycle arrest in multiple human colon cancer cells. Herein, using isogenic variants of HCT116 human colon cancer cells, we investigated the effects of p53, Bax and p21 on the apoptosis and cell cycle arrest induced by different 5OH-PMFs. Annexin V/PI co-staining assay demonstrated that 5HHMF and 5HTMF significantly induced apoptosis in HCT116 (p53 +/+) cells, but not in HCT116 (p53 −/−) cells. Further more, 5HHMF and 5HTMF significantly induced apoptosis in HCT116 (Bax +/−) cells, while their pro-apoptotic effects on HCT116 (Bax −/−) cells were marginal. All three 5OH-PMFs increased G0/G1 cell population of HCT116 (p53 +/+) cells, and these effects were abolished in HCT116 (p53 −/−) and HCT116 (p21 −/−) cells. Immunoblotting analysis showed that 5HHMF and 5HTMF increased the levels of cleaved caspase-3, cleaved PARP in both HCT116 (p53 +/+) and HCT116 (Bax +/−) cells, and these effects were much weaker in HCT116 (p53 −/−) and HCT116 (Bax −/−) cells. Taken together, our results demonstrated that 5OH-PMFs, especially 5HHMF and 5HTMF induce apoptosis and cell cycle arrest by p53, Bax and p21 dependent mechanisms.

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The p53 tumor suppressor network in cancer and the therapeutic modulation of cell death

Cited by 50 publications

References 164 publications

NSP 5a3a: A Potential Novel Cancer Target in Head and Neck Carcinoma

NSP 5a3a: A Potential Novel Cancer Target in Head and Neck Carcinoma

AMPK activation—protean potential for boosting healthspan

The p53‐, Bax‐ and p21‐dependent inhibition of colon cancer cell growth by 5‐hydroxy polymethoxyflavones

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