MSH3 Mediates Sensitization of Colorectal Cancer Cells to Cisplatin, Oxaliplatin, and a Poly(ADP-ribose) Polymerase Inhibitor

Takahashi, Masanobu; Koi, Minoru; Balaguer, Francesc; Boland, C. Richard; Goel, Ajay

doi:10.1074/jbc.m110.198804

Cited by 79 publications

(80 citation statements)

References 40 publications

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“…Therefore, caution must be exerted in interpreting the lower staging and the better outcome of cancers with MSH3 loss as the result of a more severe mutator phenotype, as protein loss or gene inactivation might directly affect tumor progression in the absence of any effect on MMR efficiency. Along this line, MSH3 deficiency has been recently shown to sensitize CRC cells to platinum drugs independently of any influence on the canonical MMR system (53).…”

Section: Discussionmentioning

confidence: 99%

MSH3 Protein Expression and Nodal Status in MLH1-Deficient Colorectal Cancers

Laghi

Bianchi

Delconte

et al. 2012

Clinical Cancer Research

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Purpose: Patients with colorectal cancers (CRC) and high microsatellite instability (MSI) have a better outcome than their chromosome-unstable counterpart. Given the heterogeneity of microsatellite-unstable CRCs, we wanted to see whether any MSI-associated molecular features are specifically associated with prognosis.Experimental Design: One hundred and nine MSI-high CRCs were typed for primary mismatch repair (MMR) defect and for secondary loss of MMR proteins. Frameshifts at seven target genes, mutations in the RAS pathway, and methylation at MLH1/CDKN2A promoters were also searched. The interplay of molecular findings with clinicopathologic features and patient survival was analyzed.Results: Of 84 MLH1-deficient CRCs, 31 (36.9%) had MSH3 and 11 (13.1%) had MSH6 loss (P < 0.001), biallelic frameshift mutations at mononucleotide repeats accounting for most (78%) MSH3 losses. As compared with MSH3-retaining cancers, MLH1-deficient tumors with MSH3 loss showed a higher number of mutated target genes (3.94 AE 1.56 vs. 2.79 AE 1.75; P ¼ 0.001), absence of nodal involvement at pathology [N0; OR, 0.11; 95% confidence interval (CI), 0.04-0.43, P < 0.001], and better disease-free survival (P ¼ 0.06). No prognostic value was observed for KRAS status and for MLH1/CDKN2A promoter methylation. The association between MSH3 loss and N0 was confirmed in an independent cohort of 71 MLH1-deficient CRCs (OR, 0.23; 95% CI, 0.06-0.83, P ¼ 0.02).Conclusions: MLH1-deficient CRCs not expressing MSH3 have a more severe MSI, a lower rate of nodal involvement, and a better postsurgical outcome.

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Section: Discussionmentioning

confidence: 99%

MSH3 Protein Expression and Nodal Status in MLH1-Deficient Colorectal Cancers

Laghi

Bianchi

Delconte

et al. 2012

Clinical Cancer Research

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“…We found no changes in the response of pancreatic cancer cells with altered RABL6A expression to treatment with gemcitabine, 5-FU, or irinotecan, whereas RABL6A loss selectively sensitized cells to oxaliplatininduced cell arrest and apoptosis. Only a few genes have been identified that influence the cellular response to oxaliplatin, including ERCC1, 29 MSH3, 30 survivin, 31,32 and NF-kB. 31 Notably, those studies were performed in other cancer cell types and the importance of those genes to PDAC is not established.…”

Section: Discussionmentioning

confidence: 99%

RABL6A Promotes Oxaliplatin Resistance in Tumor Cells and Is a New Marker of Survival for Resected Pancreatic Ductal Adenocarcinoma Patients

et al. 2013

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Pancreatic ductal adenocarcinoma (PDAC) is characterized by early recurrence following pancreatectomy, rapid progression, and chemoresistance. Novel prognostic and predictive biomarkers are urgently needed to both stratify patients for clinical trials and select patients for adjuvant therapy regimens. This study sought to determine the biological significance of RABL6A (RAB, member RAS oncogene family-like protein 6 isoform A), a novel pancreatic protein, in PDAC. Analyses of RABL6A protein expression in PDAC specimens from 73 patients who underwent pancreatic resection showed that RABL6A levels are altered in 74% of tumors relative to adjacent benign ductal epithelium. Undetectable RABL6A expression, found in 7% (5/73) of patients, correlated with improved overall survival (range 41 to 118 months with 3/5 patients still living), while patients with RABL6A expression had a worse outcome (range 3.3 to 100 months, median survival 20.3 months) (P = 0.0134). In agreement with those findings, RABL6A expression was increased in pancreatic cancer cell lines compared to normal pancreatic epithelial cells, and its knockdown inhibited pancreatic cancer cell proliferation and induced apoptosis. Moreover, RABL6A depletion selectively sensitized cells to oxaliplatin-induced arrest and death. This work reveals that RABL6A promotes the proliferation, survival, and oxaliplatin resistance of PDAC cells, whereas its loss is associated with extended survival in patients with resected PDAC. Such data suggest RABL6A is a novel biomarker of PDAC and potential target for anticancer therapy.

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“…HCT116 cells that were MMR-corrected by transfer of chromosome 3 (HCT116ϩChr.3) or transfer of chromosomes 3 and 5 (HCT116ϩChr.3ϩ5) were gifted by Ajay Goel (39). All cells were grown in McCoy's 5A medium with 10% fetal bovine serum (FBS), penicillin (100 units/ml), and streptomycin (100 g/ml).…”

Section: Methodsmentioning

confidence: 99%

Modeling the Etiology of p53-mutated Cancer Cells

Perez

Duan

Kim

et al. 2016

Journal of Biological Chemistry

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p53 gene mutations are among the most common alterations in cancer. In most cases, missense mutations in one TP53 allele are followed by loss-of-heterozygosity (LOH), so tumors express only mutant p53. TP53 mutations and LOH have been linked, in many cases, with poor therapy response and worse outcome. Despite this, remarkably little is known about how TP53 point mutations are acquired, how LOH occurs, or the cells involved. Nutlin-3a occupies the p53-binding site in MDM2 and blocks p53-MDM2 interaction, resulting in the stabilization and activation of p53 and subsequent growth arrest or apoptosis. We leveraged the powerful growth inhibitory activity of Nutlin-3a to select p53-mutated cells and examined how TP53 mutations arise and how the remaining wild-type allele is lost or inactivated. Mismatch repair (MMR)-deficient colorectal cancer cells formed heterozygote (p53 wild-type/mutant) colonies when cultured in low doses of Nutlin-3a, whereas MMR-corrected counterparts did not. Placing these heterozygotes in higher Nutlin-3a doses selected clones in which the remaining wild-type TP53 was silenced. Our data suggest silencing occurred through a novel mechanism that does not involve DNA methylation, histone methylation, or histone deacetylation. These data indicate MMR deficiency in colorectal cancer can give rise to initiating TP53 mutations and that TP53 silencing occurs via a copy-neutral mechanism. Moreover, the data highlight the use of MDM2 antagonists as tools to study mechanisms of TP53 mutation acquisition and wild-type allele loss or silencing in cells with defined genetic backgrounds.p53 is a stress-responsive tumor suppressor encoded by the TP53 gene. TP53 mutations are among the most common alterations in cancer (1). In most cases, missense mutations in one TP53 allele are followed by loss-of-heterozygosity (LOH), 2 so tumors express only mutant p53. TP53 mutations and LOH have been linked, in many cases, with poor therapy response, increased tumor aggressiveness, and decreased long term survival (2-5). Despite this, remarkably little is known about how TP53 point mutations are acquired, how LOH occurs, or the cells involved.Genomic instability is a hallmark of colorectal cancer (CRC) and is divided into the following two classes: chromosome instability (CIN) and microsatellite instability (MSI) (6 -9). Tumors with CIN include most (ϳ85%) of all CRCs and are characterized by gross karyotypic changes, including alterations in chromosome number and structure (8). The CIN phenotype appears to result, at least in part, from truncating mutations in the tumor-suppressor protein adenomatous polyposis coli, a protein that controls proper chromosome segregation in mitosis (6,8). Tumors with MSI account for the remaining 15% of CRCs. MSI tumors, as the name implies, are characterized by rapid changes (instability) in the length of short repetitive microsatellite sequences in the genome (10). In contrast to CIN, MSI tumors have a relatively stable karyotype, but instead harbor multiple frameshift and missense mu...

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MSH3 Mediates Sensitization of Colorectal Cancer Cells to Cisplatin, Oxaliplatin, and a Poly(ADP-ribose) Polymerase Inhibitor

Cited by 79 publications

References 40 publications

MSH3 Protein Expression and Nodal Status in MLH1-Deficient Colorectal Cancers

MSH3 Protein Expression and Nodal Status in MLH1-Deficient Colorectal Cancers

RABL6A Promotes Oxaliplatin Resistance in Tumor Cells and Is a New Marker of Survival for Resected Pancreatic Ductal Adenocarcinoma Patients

Modeling the Etiology of p53-mutated Cancer Cells

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