Regulation of p53 Expression in Response to 5-Fluorouracil in Human Cancer RKO Cells

Ju, Jingfang; Schmitz, John C.; Song, Bo; Kudo, Kenji; Chu, Edward

doi:10.1158/1078-0432.ccr-06-2890

Cited by 40 publications

(34 citation statements)

References 39 publications

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“…As recently reported, genotoxic stress increases the amount of SESNs, and this effect leads to AMPK activation (30). Our results show that paclitaxel treatment increased the acetylation of p53 at Lys-379, the phosphorylation of p53 at Ser 15, which are known markers of genotoxic stress (34,35), and the amount of SESN1, SESN2, and SESN3 in a timeand dose-dependent manner in both cell lines. Paclitaxel treatment also resulted in increased phosphorylation of AMPKa at Thr-172, in a time-and dose-dependent manner.…”

Section: Paclitaxel Activates Ampk and Inhibits Mtor In Mcf-7 Breast supporting

confidence: 85%

Metformin Amplifies Chemotherapy-Induced AMPK Activation and Antitumoral Growth

Rocha

Dias

Ropelle

et al. 2011

Clinical Cancer Research

259

182

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Purpose: Metformin is a widely used antidiabetic drug whose anticancer effects, mediated by the activation of AMP-activated protein kinase (AMPK) and reduction of mTOR signaling, have become noteworthy. Chemotherapy produces genotoxic stress and induces p53 activity, which can cross-talk with AMPK/mTOR pathway. Herein, we investigate whether the combination of metformin and paclitaxel has an effect in cancer cell lines.Experimental Design: Human tumors were xenografted into severe combined immunodeficient (SCID) mice and the cancer cell lines were treated with only paclitaxel or only metformin, or a combination of both drugs. Western blotting, flow cytometry, and immunohistochemistry were then used to characterize the effects of the different treatments.Results: The results presented herein show that the addition of metformin to paclitaxel leads to quantitative potentialization of molecular signaling through AMPK and a subsequent potent inhibition of the mTOR signaling pathway. Treatment with metformin and paclitaxel resulted in an increase in the number of cells arrested in the G 2 -M phase of the cell cycle, and decreased the tumor growth and increased apoptosis in tumor-bearing mice, when compared with individual drug treatments.Conclusion: We have provided evidence for a convergence of metformin and paclitaxel induced signaling at the level of AMPK. This mechanism shows how different drugs may cooperate to augment antigrowth signals, and suggests that target activation of AMPK by metformin may be a compelling ally in cancer treatment. Clin Cancer Res; 17(12); 3993-4005. Ó2011 AACR.

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Section: Paclitaxel Activates Ampk and Inhibits Mtor In Mcf-7 Breast supporting

confidence: 85%

Metformin Amplifies Chemotherapy-Induced AMPK Activation and Antitumoral Growth

Rocha

Dias

Ropelle

et al. 2011

Clinical Cancer Research

259

182

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“…In this regard, it has recently become evident that MMR-deficient tumors are often resistant to treatment with 5-FU, the first-line standard therapeutic for colorectal cancer (Ragnhammar et al, 2001), a clinical feature that is consistent with the phenotype displayed by the same type of cancer cells in culture (Meyers et al, 2001;Arnold et al, 2003;Ju et al, 2007;Wang et al, 2007). Indeed, it has been shown that the MMR system plays a prominent role in the detection and removal of fluoropyrimidine-induced lesions (Meyers et al, 2001;Meyers et al, 2003Meyers et al, , 2005.…”

Section: Discussionmentioning

confidence: 98%

“…Treatment of patients with MMR-deficient colorectal tumors has proven to be difficult using conventional chemotherapeutic regiments as those tumors are reported to be insusceptible to a variety of drug classes including antimetabolites, topoisomerase inhibitors, and most platinum-based agents (Meyers et al, 2001;Ragnhammar et al, 2001;Claij and Te Riele, 2002;Arnold et al, 2003;Ju et al, 2007;Wang et al, 2007). Because we have shown that a partial reduction of ATR or Chk1 protein levels renders MMR-deficient colorectal cancer cells more sensitive to genotoxic insults, we tested if these cells were also more sensitive to the most commonly used, first-line chemotherapeutic drug for colorectal cancer, 5-FU.…”

Section: Atr or Chk1 Partial Knockdown In Mmr-deficient Background Lementioning

confidence: 99%

Reduced ATR or Chk1 Expression Leads to Chromosome Instability and Chemosensitization of Mismatch Repair–deficient Colorectal Cancer Cells

Jardim¹,

Wang²,

Furumai³

et al. 2009

MBoC

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Genomic instability in colorectal cancer is categorized into two distinct classes: chromosome instability (CIN) and microsatellite instability (MSI). MSI is the result of mutations in the mismatch repair (MMR) machinery, whereas CIN is often thought to be associated with a disruption in the APC gene. Clinical data has recently shown the presence of heterozygous mutations in ATR and Chk1 in human cancers that exhibit MSI, suggesting that those mutations may contribute to tumorigenesis. To determine whether reduced activity in the DNA damage checkpoint pathway would cooperate with MMR deficiency to induce CIN, we used siRNA strategies to partially decrease the expression of ATR or Chk1 in MMR-deficient colorectal cancer cells. The resultant cancer cells display a typical CIN phenotype, as characterized by an increase in the number of chromosomal abnormalities. Importantly, restoration of MMR proficiency completely inhibited induction of the CIN phenotype, indicating that the combination of partial checkpoint blockage and MMR deficiency is necessary to trigger CIN. Moreover, disruption of ATR and Chk1 in MMR-deficient cells enhanced the sensitivity to treatment with the commonly used colorectal chemotherapeutic compound, 5-fluorouracil. These results provide a basis for the development of a combination therapy for those cancer patients. INTRODUCTIONEukaryotic cells are continuously exposed to endogenous and exogenous insults capable of damaging DNA. To maintain the integrity of their genomes, cells have evolved a series of sophisticated and complex signaling networks that allow cells to respond to genotoxic injury. Such responses include recognition of DNA lesions, activation of cell cycle checkpoints and DNA repair mechanisms, and, in the event of irreparable damage, initiation of apoptosis. Defects in many of these surveillance mechanisms result in the inability of cells to properly process genomic stresses, often leading to genomic instability and subsequently tumorigenesis. Genomic instability can be divided into two clinically distinct classes that have been extensively studied in colorectal cancers: chromosome instability (CIN) and microsatellite instability (MSI) (Kinzler and Vogelstein, 1996;Harfe and Jinks-Robertson, 2000;Rajagopalan et al., 2003;Rustgi, 2007). Tumors with CIN comprise ϳ85% of all colorectal cancers and are characterized by gross karyotypic changes exhibiting abnormalities in chromosome structure and number (Rajagopalan et al., 2003). The pathway leading to the development of CIN is not currently clear but it has been correlated with truncations in the adenomatous polyposis coli (APC) protein (Kinzler and Vogelstein, 1996;Rajagopalan et al., 2003). Tumors with MSI account for the remaining 15% of colorectal cancers. In contrast to CIN tumors, MSI tumors have a relatively stable karyotype and harbor anomalies at the nucleotide level, resulting in frameshift and missense mutations that disrupt the normal function of proto-oncogenes and tumor suppressors. This type of instability has been dir...

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“…Moreover, recent studies have implicated Akt in the down-regulation of p53 via MDM2, which is phosphorylated by Akt at different sites resulting in its activation (49). This view was, in part, addressed in a recent study by Ju et al (43), which demonstrates that the induced expression of p53 in RKO cells is controlled at the post-translational level after treatment with doxorubicin, whereas p53 mRNA levels do not change by exposure to the anticancer drug. Our results also identify the SPHK-mediated activation of the Akt pathway as a mechanism of cellular survival and chemoresistance in colon cancer cells, which suggests that inhibition of the Akt pathway by an SPHK inhibitor or SPHK siRNAs is a possible strategy to overcome L-OHP resistance.…”

Section: Discussionmentioning

confidence: 99%