Inability of p53-reactivating compounds Nutlin-3 and RITA to overcome p53 resistance in tumor cells deficient in p53Ser46 phosphorylation

Ma, Teng; Yamada, Seiichi; Ichwan, Solachuddin Jauhari Arief; Iseki, Sachiko; Ohtani, Kiyoshi; Otsu, Megumi; Ikeda, Masa‐Aki

doi:10.1016/j.bbrc.2011.11.161

Cited by 15 publications

(11 citation statements)

References 32 publications

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“…Indeed, the inhibition of Wip1 fortified the effect of MDM2 antagonists alone on p53 activation [162]. Similar results were obtained by others [163, 164]. These findings emphasize the therapeutic potential of negative regulators of p53 such as MDM2, as well as other negative regulators and opens new possibilities of a multitarget chemotherapy in tumors harboring wt-p53.…”

Section: Agents Interrupting the Mdm2-p53-interactionsupporting

confidence: 74%

“…It efficiently inhibited the p53 pathway by dephosphorylation of p53 at its transactivating domain Ser15 as well as by dephosphorylation of MDM2. Therefore, Wip1 promoted recovery from the G2 checkpoint and contributed to the termination of DNA damage response [162, 163, 164]. These facts affirm the necessity to decode the entire p53 interaction network as it would open new fields of research of novel chemotherapeutic agents.…”

Section: Agents Interrupting the Mdm2-p53-interactionmentioning

confidence: 99%

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The role of p53 in cancer drug resistance and targeted chemotherapy

et al. 2016

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Cancer has long been a grievous disease complicated by innumerable players aggravating its cure. Many clinical studies demonstrated the prognostic relevance of the tumor suppressor protein p53 for many human tumor types. Overexpression of mutated p53 with reduced or abolished function is often connected to resistance to standard medications, including cisplatin, alkylating agents (temozolomide), anthracyclines, (doxorubicin), antimetabolites (gemcitabine), antiestrogenes (tamoxifen) and EGFR-inhibitors (cetuximab). Such mutations in the TP53 gene are often accompanied by changes in the conformation of the p53 protein. Small molecules that restore the wild-type conformation of p53 and, consequently, rebuild its proper function have been identified. These promising agents include PRIMA-1, MIRA-1, and several derivatives of the thiosemicarbazone family. In addition to mutations in p53 itself, p53 activity may be also be impaired due to alterations in p53s regulating proteins such as MDM2. MDM2 functions as primary cellular p53 inhibitor and deregulation of the MDM2/p53-balance has serious consequences. MDM2 alterations often result in its overexpression and therefore promote inhibition of p53 activity. To deal with this problem, a judicious approach is to employ MDM2 inhibitors. Several promising MDM2 inhibitors have been described such as nutlins, benzodiazepinediones or spiro-oxindoles as well as novel compound classes such as xanthone derivatives and trisubstituted aminothiophenes. Furthermore, even naturally derived inhibitor compounds such as a-mangostin, gambogic acid and siladenoserinols have been discovered. In this review, we discuss in detail such small molecules that play a pertinent role in affecting the p53-MDM2 signaling axis and analyze their potential as cancer chemotherapeutics.

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Section: Agents Interrupting the Mdm2-p53-interactionsupporting

confidence: 74%

Section: Agents Interrupting the Mdm2-p53-interactionmentioning

confidence: 99%

The role of p53 in cancer drug resistance and targeted chemotherapy

et al. 2016

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“…RITA has also been shown to be effective in a multiple myeloma cells independently of p53 [79,80] and in cell types expressing mutant p53 protein [81]. These results are in line with our observations that RITA can induce architectural remodeling independently of p53 status in cancer cells [82].…”

Section: Discussionsupporting

confidence: 91%

p53 CRISPR Deletion Affects DNA Structure and Nuclear Architecture

Rangel‐Pozzo

Booth

et al. 2020

JCM

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The TP53 gene is a key tumor suppressor. Although the tumor suppressor p53 was one of the first to be characterized as a transcription factor, with its main function potentiated by its interaction with DNA, there are still many unresolved questions about its mechanism of action. Here, we demonstrate a novel role for p53 in the maintenance of nuclear architecture of cells. Using three-dimensional (3D) imaging and spectral karyotyping, as well as super resolution microscopy of DNA structure, we observe significant differences in 3D telomere signatures, DNA structure and DNA-poor spaces as well gains or losses of chromosomes, between normal and tumor cells with CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)-deleted or wild-type TP53. Additionally, treatment with Nutlin-3 results in differences in nuclear architecture of telomeres in wild-type but not in p53 knockout MCF-7 (Michigan Cancer Foundation-7) cells. Nutlin-3 binds to the p53-binding pocket of mouse double minute 2 (MDM2) and blocks the p53-MDM2 interaction. Moreover, we demonstrate that another p53 stabilizing small molecule, RITA (reactivation of p53 and induction of tumor cell apoptosis), also induces changes in 3D DNA structure, apparently in a p53 independent manner. These results implicate p53 activity in regulating nuclear organization and, additionally, highlight the divergent effects of the p53 targeting compounds Nutlin-3 and RITA.

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“…7 It would be of interest to evaluate the role of Pin1 in this pathway, given that Ser46 phosphorylation appears to be a common requirement for the cytotoxic action of both Nutlin and RITA in cancer cells. 42 …”

Section: Discussionmentioning

confidence: 99%

The prolyl-isomerase Pin1 activates the mitochondrial death program of p53

et al. 2012

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In response to intense stress, the tumor protein p53 (p53) tumor suppressor rapidly mounts a direct mitochondrial death program that precedes transcription-mediated apoptosis. By eliminating severely damaged cells, this pathway contributes to tumor suppression as well as to cancer cell killing induced by both genotoxic drugs and non-genotoxic p53-reactivating molecules. Here we have explored the role had in this pathway by the prolyl-isomerase Pin1 (peptidylprolyl cis/trans isomerase, NIMA-interacting 1), a crucial transducer of p53's phosphorylation into conformational changes unleashing its pro-apoptotic activity. We show that Pin1 promotes stress-induced localization of p53 to mitochondria both in vitro and in vivo. In particular, we demonstrate that upon stress-induced phosphorylation of p53 on Ser46 by homeodomain interacting protein kinase 2, Pin1 stimulates its mitochondrial trafficking signal, that is, monoubiquitination. This pathway is induced also by the p53-activating molecule RITA, and we demonstrate the strong requirement of Pin1 for the induction of mitochondrial apoptosis by this compound. These findings have significant implications for treatment of p53-expressing tumors and for prospective use of p53-activating compounds in clinics.

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Inability of p53-reactivating compounds Nutlin-3 and RITA to overcome p53 resistance in tumor cells deficient in p53Ser46 phosphorylation

Cited by 15 publications

References 32 publications

The role of p53 in cancer drug resistance and targeted chemotherapy

The role of p53 in cancer drug resistance and targeted chemotherapy

p53 CRISPR Deletion Affects DNA Structure and Nuclear Architecture

The prolyl-isomerase Pin1 activates the mitochondrial death program of p53

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