New Insights into p53 Signaling and Cancer Cell Response to DNA Damage: Implications for Cancer Therapy

Mirzayans, Razmik; Andrais, Bonnie; Scott, April; Murray, David

doi:10.1155/2012/170325

Cited by 214 publications

(196 citation statements)

References 119 publications

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“…Not surprisingly, the p53-regulated miR34a has reduced expression levels in liver tumors (4). Consistent with a recent publication that describes the ability of miR34a to stimulate the p53 pathway in cancer cells lacking p53 (25), we observed increased expression levels of the p53-related genes CHEK2, CDKN1A, BID, CASP3, and CCNG2 (21,26) in the liver tumors of mice dosed a single time with MRX34. This result suggests that the potency of MRX34 might derive at least partially from its capacity to stimulate the p53 pathway in cancer cells that lack p53 activity as is the case with the Hep3B cell line.…”

Section: Discussionsupporting

confidence: 90%

Systemic Delivery of a miR34a Mimic as a Potential Therapeutic for Liver Cancer

Daige

Wiggins

Priddy

et al. 2014

Molecular Cancer Therapeutics

143

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miR34a is a tumor-suppressor miRNA that functions within the p53 pathway to regulate cell-cycle progression and apoptosis. With apparent roles in metastasis and cancer stem cell development, miR34a provides an interesting opportunity for therapeutic development. A mimic of miR34a was complexed with an amphoteric liposomal formulation and tested in two different orthotopic models of liver cancer. Systemic dosing of the formulated miR34a mimic increased the levels of miR34a in tumors by approximately 1,000-fold and caused statistically significant decreases in the mRNA levels of several miR34a targets. The administration of the formulated miR34a mimic caused significant tumor growth inhibition in both models of liver cancer, and tumor regression was observed in more than one third of the animals. The antitumor activity was observed in the absence of any immunostimulatory effects or dose-limiting toxicities. Accumulation of the formulated miR34a mimic was also noted in the spleen, lung, and kidney, suggesting the potential for therapeutic use in other cancers. Mol Cancer Ther; 13(10); 2352-60. Ó2014 AACR.

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Section: Discussionsupporting

confidence: 90%

Systemic Delivery of a miR34a Mimic as a Potential Therapeutic for Liver Cancer

Daige

Wiggins

Priddy

et al. 2014

Molecular Cancer Therapeutics

143

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“…On the other hand, it has also been reported that p21 functions as a potent antiapoptotic factor, acting at different levels of the death cascade. 30,31 Therefore the overexpression of p21 in our samples could also be linked to the abnormal behavior of PIRC rat NM in response to an apoptotic stimulus as we observed in our samples (see below).…”

Section: Discussionsupporting

confidence: 55%

Multiple mucin depleted foci, high proliferation and low apoptotic response in the onset of colon carcinogenesis of the PIRC rat, mutated in Apc

Femia

Luceri

Soares³

et al. 2014

Intl Journal of Cancer

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PIRC rats (F344/NTac-Apc am1137 ) mutated in the Apc gene spontaneously develop colon tumors thus mimicking familial adenomatous polyposis (FAP) and sporadic colorectal cancer (CRC) more closely than Apc-based rodent models developing tumors mostly in the small intestine. To understand whether microscopic dysplastic lesions precede the development of macroscopic tumors, PIRC rat colon was examined for the presence of mucin depleted foci (MDF), microadenomas of the rodent and human colon. Few MDF (about 4/animal) were already present in 1-month-old rats and their number rapidly increases to about 250 in 8-month-old rats. These lesions showed Wnt signaling activation (nuclear b-catenin accumulation) and were dramatically decreased by sulindac (320 ppm), a drug with chemopreventive activity (MDF/rat at 4 months: 156 6 8 and 38 6 6 in controls and sulindac-treated rats, respectively, means 6 SE, p < 0.001). Since altered proliferation and apoptosis could underlie the early phases of carcinogenesis, we studied these processes in the apparently normal colon mucosa (NM) of 1-month-old PIRC and wt rats. Colon proliferation (PCNA expression) was significantly higher in PIRC rats. Notably, PIRC rat NM showed resistance to apoptosis since it sustained proliferation and had lower apoptosis after a cytotoxic insult with 1,2 dimethylhydrazine. Gene expression of Myc, p21, Birc5, Ogg1, Apex1 and Sod2 were significantly up-regulated in the NM of PIRC rat. The overall results put forward PIRC rat as useful model of colon carcinogenesis, either to study the process itself or to test in vivo chemopreventive agents in both short-and long-term studies.Mutations in the Apc gene, responsible for the inherited predisposition to intestinal carcinogenesis in familial adenomatous polyposis (FAP) and present in the majority of sporadic colorectal cancers (CRC), are considered early, necessary events in the development of the disease. 1 Rodent models carrying mutations in Apc have been thus developed and widely used. 2,3 However, at variance with human pathology, the majority of these strains, including Apc Min (Min) mice, develops tumors predominantly in the small intestine and not in the colon. [2][3][4] This characteristic is a considerable drawback given the inherent diversity of these two parts of the intestine in terms of anatomy, lumen environment, physiology and propensity to tumor development. [2][3][4] Few years ago, the PIRC rat (Polyposis In the Rat Colon) with a germline mutation in one allele of the Apc gene (F344/NTac-Apc am1137 ) has been described. 5 Notably, at variance with pre-existing Apcbased mouse models, PIRC rats spontaneously develop tumors in the small intestine but also in the colon, thus mimicking more closely FAP and CRC and potentially standing for as a robust model of colon cancer. 5 Here we were interested in the early phases of PIRC rat colon carcinogenesis studying (i) the presence and the biology of early-appearing precancerous lesions in the colon and (ii) the morphologically normal mucosa (NM). Small ad...

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“…If DNA DSBs are not repaired, ATM additionally phosphorylates MDM2 and p53 at Ser15 (Canman et al, 1998) leading to stabilization and activation of p53, which regulates numerous p53 target genes including Cdk inhibitor p21, proapoptotic proteins BAX, PUMA, and NOXA, and results in cell cycle arrest or apoptosis (Mirzayans et al, 2012). However, my lab has also taken the lead in demonstrating a novel role of ATM in response to DNA replication stress in the absence of DSBs.…”

Section: Discussionmentioning

confidence: 99%