Mutant<i>PIK3CA</i>-Bearing Colon Cancer Cells Display Increased Metastasis in an Orthotopic Model

Guo, Xiaoning; Rajput, Ashwani; Rose, Rebecca; Hauser, Jennie; Beko, Alexander; Kuropatwinski, Karen K.; LeVea, Charles; Hoffman, Robert M.; Brattain, Michael G.; Wang, Jing

doi:10.1158/0008-5472.can-07-0049

Cited by 57 publications

(56 citation statements)

References 44 publications

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“…Analysis of isogenic HCT116 cell lines expressing wild-type or mutant PIK3CA revealed enhanced growth factor-independent cell proliferation and resistance against apoptosis induction by TRAIL and growth factor deprivation in the mutant PIK3CA cells. 4,21 In accordance with the study of Guo et al, 21 which traced back apoptosis resistance of growth factor-deprived HCT116-PIK3CA-mut cells to downregulation of Bax expression, we found no major differences in the recruitment and activation of caspase-8 by CD95 and TRAIL death receptor between wild-type and mutant PIK3CA-expressing isogenic HCT116 cells (Figures 1 and 2). Thus, resistance against death receptor-induced apoptosis in the HCT116-PIK3CA-mut model is largely dependent on mechanisms acting downstream of death receptor-associated caspase-8 maturation.…”

Section: Discussionsupporting

confidence: 91%

“…Indeed, a recent publication showed that expression of Bax was severely reduced in HCT116-PIK3CA-mut cells. 21 We, therefore, investigated next whether the loss of Bax expression is sufficient to protect HCT116 cells from TRAIL-and CD95L-induced apoptosis. Although HCT116 cells harboring a wild type and a mutated PIK3CA allele were not as TRAIL/ CD95L sensitive as HCT116-PIK3CA-wt cells, they nevertheless showed higher sensitivity than the almost completely protected HCT116-PIK3CA-mut cells (data not shown).…”

Section: Resultsmentioning

confidence: 99%

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Mutant PIK3CA licenses TRAIL and CD95L to induce non-apoptotic caspase-8-mediated ROCK activation

et al. 2010

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Constitutively active PI3K catalytic subunit a (PIK3CA) interfered with apoptosis induction downstream of death receptorsignaling complex formation allowing robust caspase-8 activation without triggering the execution steps of apoptosis. In mutant PIK3CA-expressing cells, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and CD95L stimulated nuclear factor kappaB (NFjB) activation, invasion, and transition to an amoeboid-like morphology. NFjB activation and adoption of amoeboid shape were inhibited by caspase-8 knockdown or FLIP-S expression, but only the cell morphology alterations required caspase-8 activity. Furthermore, we identified caspase-8-mediated, caspase-3-independent cleavage of the protein kinase rho-associated, coiled-coil containing protein kinase 1 as a novel mechanism for acquiring amoeboid shape and enhanced invasiveness in response to TRAIL and CD95L. Taken together, we provide evidence that mutated PIK3CA converts the 'tumor surveillance' activity of cancer cell-expressed death receptors and caspase-8 toward tumor promotion.

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Section: Discussionsupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Mutant PIK3CA licenses TRAIL and CD95L to induce non-apoptotic caspase-8-mediated ROCK activation

et al. 2010

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“…To investigate and quantitate the tumor burdens in the lungs of the animals, RNA was extracted from lung of each mouse, and real-time PCR analysis was done using human-specific GAPDH primer, because the level of human GAPDH mRNA expression in each sample reflects the tumor burden in the lungs of the mice. 21,22 Mice lung tissues were lysed and analyzed for human (tumor) and mouse (control) GAPDH transcripts. Real-time PCR quantitation showed that the number of lung metastasis was significantly increased in the lungs of mice carrying PRL-3 cells (p ¼ 0.00135; Fig.…”

Section: Prl-3 Induces Lung Metastasis In Vivomentioning

confidence: 99%

Phosphatase of regenerating liver‐3 promotes migration and invasion by upregulating matrix metalloproteinases‐7 in human colorectal cancer cells

Lee

Han

Yun

et al. 2012

Intl Journal of Cancer

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Phosphatase of regenerating liver (PRL)-3, a member of a subgroup of protein tyrosine phosphatases that can stimulate the degradation of the extracellular matrix, is over-expressed in metastatic colorectal cancer (CRC) relative to primary tumors. To determine whether PRL-3-induced enhancement of migration and invasion is dependent on the expression of matrix metalloproteinases (MMPs), PRL-3 was expressed in DLD-1 human CRC cells. The motility, migration and invasion characteristics of the cells were examined, and metastasis to the lung was confirmed in a nude mouse using PRL-3-overexpressing DLD-1 cells [DLD-1 (PRL-3)]. Migration and invasion of the cells were inhibited by phosphatase and farnesyltransferase inhibitors. Expression of MMPs was enhanced 3-to 10-fold in comparison to control cells, and migration and invasion were partially inhibited by small interfering RNA (siRNA) knockdown of MMP-2, -13 or -14. Importantly, siRNA knockdown of MMP-7 completely inhibited the migration and invasion of DLD-1 (PRL-3) cells, whereas overexpression of MMP-7 increased migration. The expression of MMP-7 was also downregulated by phosphatase and farnesyltransferase inhibitors. It was found that PRL-3 induced MMP-7 through oncogenic pathways including PI3K/AKT and ERK and that there is a relationship between the expression of PRL-3 and MMP-7 in human tumor cell lines. The expression of MMP-13 and -14 was very sensitive to the inhibition of farnesyltransferase; however, the migration and invasion of DLD-1 (PRL-3) cells did not strongly depend on the expression of MMP-13 or -14. These results suggest that the migration and invasion of PRL-3-expressing CRC cells depends primarily on the expression of MMP-7.

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“…The increased copy number of the PIK3CA gene is associated with increased PIK3CA transcription, p110· protein expression and PI3K activity in ovarian cancer (9). It has been reported that aberrant PI3-kinase activation plays important roles in sustaining processes important to malignancy, including cell proliferation, adhesion, survival and motility (9,(12)(13)(14)(15)(16)(17)(18). PIK3CA allows Ser/Thr kinase (Akt), which is one critical downstream target of this signaling pathway, to be phosphorylated by PDK1 and PDK2 at Thr308 and Ser473, respectively (12).…”

Section: Introductionmentioning

confidence: 99%

Overexpression of PIK3CA is associated with lymph node metastasis in esophageal squamous cell carcinoma

Akagi

Miyashita²,

Makino³

et al. 2009

Int J Oncol

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Abstract. The genomic region containing PIK3CA was found to be amplified in esophageal squamous cell carcinoma (ESCC) tissue. PIK3CA at 3q26, which encodes the p110· catalytic subunit of phosphatidylinositol (PI) 3-kinase, is a unique intracellular signal transducer characterized by its lipid substrate specificity. In order to characterize PIK3CA in ESCC, we investigated hot-spot mutations in exons 1, 9 and 20, the copy number gain, the expression levels of mRNA and protein. Analysis in exon 9 of the PIK3CA gene revealed mutation in 7.7% (4 of 52) of ESCC samples. No mutation was detected in either exon 1 or exon 20. Copy number amplifications of PIK3CA were found in 12 of the 45 patients (26.7%). PIK3CA mRNAs were examined in 37 ESCC patients as determined by quantitative RT-PCR and the mean mRNA level of PIK3CA in ESCC tissues was 2.61-fold higher compared with that in corresponding non-tumorous esophageal epithelia (P<0.001). Immunohistochemically, positive immunoreaction for PIK3CA was detectable in 33 of 66 (50.0%) ESCC cases, while it was not detectable in the remaining 33 cases. Furthermore, comparing the cases with negative staining with those with positive staining for PIK3CA, the presence of node metastasis was significantly correlated with those with positive staining (P<0.05). This study is the first report providing comprehensive analysis of PIK3CA expression in ESCC. These results indicate that PIK3CA may play a crucial role in the development of ESCC and serve as an indicator for lymph node metastasis.

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MutantPIK3CA-Bearing Colon Cancer Cells Display Increased Metastasis in an Orthotopic Model

Cited by 57 publications

References 44 publications

Mutant PIK3CA licenses TRAIL and CD95L to induce non-apoptotic caspase-8-mediated ROCK activation

Mutant PIK3CA licenses TRAIL and CD95L to induce non-apoptotic caspase-8-mediated ROCK activation

Phosphatase of regenerating liver‐3 promotes migration and invasion by upregulating matrix metalloproteinases‐7 in human colorectal cancer cells

Overexpression of PIK3CA is associated with lymph node metastasis in esophageal squamous cell carcinoma

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