Mutational Targets in Colorectal Cancer Cells with Microsatellite Instability

Bertholon, Jacques; Wang, Qing; Galmarini, Carlos M.; Puisieux, Alain

doi:10.1007/s10689-005-2573-5

Cited by 22 publications

(16 citation statements)

References 33 publications

(31 reference statements)

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“…A potent tumor suppressor, loss-of-function mutations of p53 correlates with chemoresistant and aggressive tumors; p53 mutation is considered to be an early step in the development of colon carcinoma (33). Here we report that pancratistatin effectively induced apoptosis and caspaseindependent cell death in human colorectal adenocarcinoma (HT-29) cells that have a loss-of-function mutation of p53.…”

Section: Discussionmentioning

confidence: 85%

Pancratistatin Selectively Targets Cancer Cell Mitochondria and Reduces Growth of Human Colon Tumor Xenografts

Griffin

Karnik

McNulty

et al. 2011

Molecular Cancer Therapeutics

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The naturally occurring Amaryllidaceae alkaloid pancratistatin exhibits potent apoptotic activity against a large panel of cancer cells lines and has an insignificant effect on noncancerous cell lines, although with an elusive cellular target. Many current chemotherapeutics induce apoptosis via genotoxic mechanisms and thus have low selectivity. The observed selectivity of pancratistatin for cancer cells promoted us to consider the hypothesis that this alkaloid targets cancer cell mitochondria rather than DNA or its replicative machinery. In this study, we report that pancratistatin decreased mitochondrial membrane potential and induced apoptotic nuclear morphology in p53-mutant (HT-29) and wild-type p53 (HCT116) colorectal carcinoma cell lines, but not in noncancerous colon fibroblast (CCD-18Co) cells. Interestingly, pancratistatin was found to be ineffective against mtDNA-depleted (r 0 ) cancer cells. Moreover, pancratistatin induced cell death in a manner independent of Bax and caspase activation, and did not alter b-tubulin polymerization rate nor cause double-stranded DNA breaks. For the first time we report the efficacy of pancratistatin in vivo against human colorectal adenocarcinoma xenografts. Intratumor administration of pancratistatin (3 mg/kg) caused significant reduction in the growth of subcutaneous HT-29 tumors in Nu/Nu mice (n ¼ 6), with no apparent toxicity to the liver or kidneys as indicated by histopathologic analysis and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling. Altogether, this work suggests that pancratistatin may be a novel mitochondria-targeting compound that selectively induces apoptosis in cancer cells and significantly reduces tumor growth.

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Section: Discussionmentioning

confidence: 85%

Pancratistatin Selectively Targets Cancer Cell Mitochondria and Reduces Growth of Human Colon Tumor Xenografts

Griffin

Karnik

McNulty

et al. 2011

Molecular Cancer Therapeutics

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“…Given that biallelic mutations in ATR or Chk1 lead to cell lethality (Brown and Baltimore, 2000;de Klein et al, 2000;Liu et al, 2000;Takai et al, 2000), it is unlikely that homozygous null mutations exist in human disease, even in late-stage malignant cells. Several clinical reports have recently demonstrated that checkpoint signaling proteins are indeed found to be heterozygously mutated in multiple types of tumors with mismatch repair deficiencies, including malignancies of the stomach, the endometrium, and the colon (Menoyo et al, 2001;Lewis et al, 2005;Bertholon et al, 2006;Kim et al, 2007;Lewis et al, 2007). However, it remains unclear how these ATR and Chk1 mutations contribute to the tumorigenic process.…”

Section: Discussionmentioning

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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“…Recently, BRCA1 is shown to regulate an MMRinduced G2/M checkpoint, which is critical for inhibition of CIN (Yamane et al, 2007). The observation of alterations of key growth regulatory genes in MMR-deficient cells such as NF1, APC, p53, K-Ras may suggest that even in the presence of MSI, tumour progression is mainly driven by a process of natural selection (Bertholon et al, 2006). MSI + colorectal carcinoma has been associated with a more favourable clinical outcome (Chung and Rustgi, 2003) that has confounded clinical studies assessing drug efficacy among colorectal cancer patients.…”

Section: Mmr Defects and Human Cancermentioning

confidence: 99%

DNA mismatch repair: Molecular mechanism, cancer, and ageing

Hsieh

Yamane

2008

Mechanisms of Ageing and Development

387

359

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DNA mismatch repair (MMR) proteins are ubiquitous players in a diverse array of important cellular functions. In its role in post-replication repair, MMR safeguards the genome correcting base mispairs arising as a result of replication errors. Loss of MMR results in greatly increased rates of spontaneous mutation in organisms ranging from bacteria to humans. Mutations in MMR genes cause hereditary nonpolyposis colorectal cancer, and loss of MMR is associated with a significant fraction of sporadic cancers. Given its prominence in mutation avoidance and its ability to target a range of DNA lesions, MMR has been under investigation in studies of ageing mechanisms. This review summarizes what is known about the molecular details of the MMR pathway and the role of MMR proteins in cancer susceptibility and ageing.

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Mutational Targets in Colorectal Cancer Cells with Microsatellite Instability

Cited by 22 publications

References 33 publications

Pancratistatin Selectively Targets Cancer Cell Mitochondria and Reduces Growth of Human Colon Tumor Xenografts

Pancratistatin Selectively Targets Cancer Cell Mitochondria and Reduces Growth of Human Colon Tumor Xenografts

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

DNA mismatch repair: Molecular mechanism, cancer, and ageing

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