IAPP-driven metabolic reprogramming induces regression of p53-deficient tumours in vivo

Venkatanarayan, Avinashnarayan; Raulji, Payal; Norton, William; Chakravarti, Deepavali; Coarfa, Cristian; Su, Xiaohua; Sandur, Santosh K.; Ramirez, Marc S.; Lee, Jaehuk; Kingsley, Charles V.; Sananikone, Eliot F.; Rajapakshe, Kimal; Naff, Katherine A.; Parker-Thornburg, Jan; Bankson, James A.; Tsai, Kenneth Y.; Gunaratne, Preethi H.; Flores, Elsa R.

doi:10.1038/nature13910

Cited by 117 publications

(174 citation statements)

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“…Enfin, il existe deux gènes apparentés à p53, p73 et p63 [55] (➜), dont les rôles se superposent en partie à ceux de p53. Ces trois gènes codent pour de multiples isoformes présentant des fonctions différentes voire opposées [4,10]. La réponse induite par p53 est donc aussi dépendante de l'équilibre entre les différentes isoformes exprimées par ces trois gènes.…”

Section: Le Triumviratunclassified

“…L'avantage sélectif que peut procurer une forte activité glycolytique implique que l'équilibre d'un organisme multicellulaire dépend du maintien d'un métabolisme respiratoire et/ou de la stricte limitation parce que celle-ci reste en dessous d'un certain seuil, soit parce que des activateurs de p53 sont mutés, p53 continue d'exercer ses fonctions conservatrices et peut alors favoriser paradoxalement la croissance tumorale [1,2,4,11,25,26]. Les mutations de p53 aggravent cette situation : elles entraînent souvent la souris p53 -/-, la régression des lymphomes T consécutive à l'activation de p63 ou p73 et l'expression de iapp, ne soit pas directement provoquée par la reprogrammation métabolique des cellules tumorales, mais par l'apoptose qui l'accompagne [10]. Une conséquence importante de la dualité fonctionnelle de p53 est que si la cellule ne « voit » pas sa transformation oncogénique, soit La régulation négative par p53 normal de la voie du mévalonate est probable mais pas établie [7,50].…”

Section: Conclusion Perspectivesunclassified

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Protéger et sévir : p53, métabolisme et suppression tumorale

Albagli

2015

Med Sci (Paris)

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Section: Le Triumviratunclassified

Section: Conclusion Perspectivesunclassified

Protéger et sévir : p53, métabolisme et suppression tumorale

Albagli

2015

Med Sci (Paris)

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“…The p63 isoforms can be placed into two groups: the transactivation domain isoforms (TAp63), which structurally resemble p53 and act as tumor suppressors; and the DN isoforms (DNp63), which bind to p53, TAp63, and TAp73 and inhibit their function, thus acting as oncogenes (22)(23)(24). Unlike DNp63, TAp63 is not expressed or is present at low levels in a variety of cancers (25,26).…”

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YAP Expression and Activity Are Suppressed by S100A7 via p65/NFκB-mediated Repression of ΔNp63

Kong

Shao

et al. 2017

Molecular Cancer Research

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In several squamous cell carcinoma (SCC) cells, it has been previously observed that induction of the S100 calcium-binding protein A7 (S100A7) is repressed by YAP via the Hippo pathway. This report now demonstrates that S100A7 also represses YAP expression and activity by DNp63 in cancer cells. Stable overexpression of S100A7 activates the NFkB pathway and inhibits the expression of DNp63. Caffeic acid phenethyl ester (CAPE), as a specific inhibitor of NFkB, counteracts the inhibitory effect of S100A7 on the expression of DNp63 and its target genes. Depletion of S100A7 significantly promotes DNp63 expression. These data indicate that S100A7 acts as a suppressor of DNp63. Mechanistic examination finds that DNp63 not only directly binds to the region of YAP promoter and induces its expression, but also inhibits the Hippo pathway and enhances YAP activity. Importantly, either the positive correlation between S100A7 and YAP phosphorylation at S127 or the negative correlation between S100A7 and DNp63 is also observed in skin SCC tissues. Chemosensitivity analysis reveals that S100A7 enhances cancer cells' resistance by inhibition of YAP expression and activity. These results demonstrate that S100A7 is an upstream modulator of the Hippo pathway and extend our understanding of S100A7 functions in cancer.Implications: S100A7 is a new upstream regulator of the Hippo signaling pathway and reduces chemosensitivity of SCC cells through inhibitions of YAP expression and activity.

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“…In cell culture assays, the TA isoforms were found to have proapoptotic functions, whereas the DN isoforms had prosurvival functions (13)(14)(15). Recently, genetically engineered mouse models have unequivocally shown that TAp63 and TAp73 are tumor suppressor genes through their abilities to regulate miRNA biogenesis, senescence, and metabolism (17-21) and that DNp63 and DNp73 are oncogenes though their activities in metabolic reprogramming (20,22). These findings are important in the context of one of the observations highlighted in the Brown and Wouters review, that is, that mutations in p53 have been shown to confer sensitivity to drugs, such as nitrogen mustard and cisplatin (23,24).…”

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“…The authors provide an argument due to the levels of cisplatin used and that may have yielded no apoptosis followed by lower colony formation. One other explanation could be the activity of the p53 family members and their isoforms, which have not been tested in this system.The p63 and p73 mouse models described above have led to an understanding of the interplay of the p53 family not only in apoptosis, but in other antitumorigenic functions, such as metabolism (20). This knowledge has allowed the design of potential novel therapies for the p53 pathway.…”

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Commentary on “Apoptosis, p53, and Tumor Cell Sensitivity to Anticancer Agents”

Flores

2016

Cancer Research

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In 1999, a review on apoptosis, p53, and tumor cell sensitivity to anticancer agents was published in Cancer Research (1). TP53 is one of the most commonly mutated tumor suppressor genes in human cancer. This review accurately encapsulates the body of data collected at the time with regard to cells lacking p53 and their sensitivity to anticancer agents using short-term assays. Importantly, the authors of this review, Brown and Wouters, stress the importance of using long-term clonogenic assays to reveal the true sensitivity of cells to anticancer agents. This review in part led to a flurry of further investigation on p53 and its role in cancer and sensitivity to radiation, chemotherapy, and other anticancer agents.The major arguments laid out by the authors of this review are: (i) short-term assays can underestimate overall cell killing; (ii) p53 status did not seem to affect the sensitivity of cells of nonhematologic origin to genotoxic stress. The conclusions were contrary to the belief in the cancer field that tumor cells bearing p53 mutations were resistant to apoptosis and to cancer treatment (2-5). This review was written as a cautionary tale for investigators moving their studies from tissue culture-based work to in vivo mouse models. Many times, moving results from cell-based assays does not translate into effective use in vivo. Although the authors made very important points regarding the use of long-term clonogenic assays to assess the sensitivity of tumor cells to genotoxic agents, what was lacking at the time of publication were in vivo knockin mouse models with the p53 mutations that are commonly detected in human cancer patients. Over the last 17 years, several mouse models with p53 point mutations have been genetically engineered (6-9); two additional p53 family members, p63 and p73, were identified and found to contribute to p53 tumor suppression (10). Using these additional mouse models, novel insights and therapies to target the p53 pathway have been made.Two landmark articles with p53 hotspot mutations corresponding to p53R175H and p53R273H provided evidence of p53-mutant gain of function in cancer (7, 9). These mice displayed a distinct tumor spectrum to mice lacking p53, and also, tumors from these mice with p53 mutations metastasized (7, 9). Generation of these models also led to the ability to reactivate p53 in p53 nullizygous mice (11) and in those with mutant p53 (12) as a means for therapy. These mouse models show distinct mechanisms for p53 tumor suppression in different tumor types. Upon reactivation of p53 in p53 nullizygous mice, induction of apoptosis was critical for regression of lymphomas, while induction of cellular senescence is the key mechanism for regression of sarcomas (11); however, in mice with a p53 missense mutation, reactivation of p53 kept tumors from progressing but did not completely cause tumor regression (12). These results clearly indicate the differences between loss of p53 and the gain-offunction and dominant-negative effects of point mutant p53. Other mouse m...

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IAPP-driven metabolic reprogramming induces regression of p53-deficient tumours in vivo

Cited by 117 publications

References 47 publications

Protéger et sévir : p53, métabolisme et suppression tumorale

Protéger et sévir : p53, métabolisme et suppression tumorale

YAP Expression and Activity Are Suppressed by S100A7 via p65/NFκB-mediated Repression of ΔNp63

Commentary on “Apoptosis, p53, and Tumor Cell Sensitivity to Anticancer Agents”

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