Interplay between oncogenic K-Ras and wild-type H-Ras in Caco2 cell transformation

Ikonomou, Georgia; Kostourou, Vassiliki; Shirasawa, Senji; Sasazuki, Takehiko; Samiotaki, Martina; Panayotou, George

doi:10.1016/j.jprot.2012.06.038

Cited by 8 publications

(8 citation statements)

References 23 publications

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“…Macropinocytosis, a highly conserved endocytic process by which extracellular fluid and its contents are internalized into cells, is stimulated by activated Ras and utilized as a unique mechanism for nutrient uptake in Ras -activated cancer cells. Here, to determine if the macropinocytosis-mediated cellular uptake of CaP-rHDL is Ras-dependent, we employed the cell lines including human glioblastoma cell lines U87 and U251, human pancreatic adenocarcinoma cell line MIA PaCa-2 ( KRas G12C mutation) and colorectal cancer cell line SW-480 ( KRas G12V mutation), all showed higher Ras activity than astrocytes, a pancreastic cell line BxPC-3 and a colon cell line Caco-2, which express wild-type KRas 32333435, for the analysis. Along with their higher Ras activity, those KRas -mutated tumour cell lines showed higher cellular association of DiI-CaP-rHDL, compared with the KRas wild-type control cell lines (Fig.…”

Section: Resultsmentioning

confidence: 99%

Lipoprotein-biomimetic nanostructure enables efficient targeting delivery of siRNA to Ras-activated glioblastoma cells via macropinocytosis

et al. 2017

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Hyperactivated Ras regulates many oncogenic pathways in several malignant human cancers including glioblastoma and it is an attractive target for cancer therapies. Ras activation in cancer cells drives protein internalization via macropinocytosis as a key nutrient-gaining process. By utilizing this unique endocytosis pathway, here we create a biologically inspired nanostructure that can induce cancer cells to ‘drink drugs' for targeting activating transcription factor-5 (ATF5), an overexpressed anti-apoptotic transcription factor in glioblastoma. Apolipoprotein E3-reconstituted high-density lipoprotein is used to encapsulate the siRNA-loaded calcium phosphate core and facilitate it to penetrate the blood–brain barrier, thus targeting the glioblastoma cells in a macropinocytosis-dependent manner. The nanostructure carrying ATF5 siRNA exerts remarkable RNA-interfering efficiency, increases glioblastoma cell apoptosis and inhibits tumour cell growth both in vitro and in xenograft tumour models. This strategy of targeting the macropinocytosis caused by Ras activation provides a nanoparticle-based approach for precision therapy in glioblastoma and other Ras-activated cancers.

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Section: Resultsmentioning

confidence: 99%

Lipoprotein-biomimetic nanostructure enables efficient targeting delivery of siRNA to Ras-activated glioblastoma cells via macropinocytosis

et al. 2017

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“…For example, in a study aimed at understanding the mechanism of FTI (farnesyl transferase inhibitor)-mediated radiosensitization in cell lines that express oncogenic KRAS, wild type HRAS, although not wild type NRAS, contributed to radiation survival in most of the KRAS mutant pancreatic and colorectal carcinoma cell lines treated [63]. Similarly, ectopic expression of KRAS G12V in the colorectal cancer cell line Caco-2 increased both the expression and activity of endogenous HRAS, and silencing of HRAS showed that oncogenic KRAS partly exerted its effects, such as enhanced invasiveness, through wild type HRAS [64]. On the other hand, Coffey and colleagues demonstrated that the presence of an oncogenic KRAS allele increased GTP-bound wild type NRAS in two human colorectal cancer cell lines, HCT116 and DLD-1, compared to their isogenic counterparts in which the mutant KRAS allele was disrupted by homologous recombination [65].…”

Section: Wild Type Ras Isoforms In Ras Mutant Cancers: Tumour Suppmentioning

confidence: 99%

The role of wild type RAS isoforms in cancer

Zhou

Der

Cox

2016

Seminars in Cell & Developmental Biology

109

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Mutationally activated RAS proteins are critical oncogenic drivers in nearly 30% of all human cancers. As with mutant RAS, the role of wild type RAS proteins in oncogenesis, tumour maintenance and metastasis is context-dependent. Complexity is introduced by the existence of multiple RAS genes (HRAS, KRAS, NRAS) and protein "isoforms" (KRAS4A, KRAS4B), by the ever more complicated network of RAS signaling, and by the increasing identification of numerous genetic aberrations in cancers that do and do not harbour mutant RAS. Numerous mouse model carcinogenesis studies and examination of patient tumours reveal that, in RAS-mutant cancers, wild type RAS proteins are likely to serve as tumour suppressors when the mutant RAS is of the same isoform. This evidence is particularly robust in KRAS mutant cancers, which often display suppression or loss of wild type KRAS, but is not as strong for NRAS. In contrast, although not yet fully elucidated, the preponderance of evidence indicates that wild type RAS proteins play a tumour promoting role when the mutant RAS is of a different isoform. In non-RAS mutant cancers, wild type RAS is recognized as a mediator of oncogenic signaling due to chronic activation of upstream receptor tyrosine kinases that feed through RAS. Additionally, in the absence of mutant RAS, activation of wild type RAS may drive cancer upon the loss of negative RAS regulators such as NF1 GAP or SPRY proteins. Here we explore the current state of knowledge with respect to the roles of wild type RAS proteins in human cancers.

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“…HRAS p.Q61R mutation has been found in urothelial bladder cancer [182]. Association between increased levels of HRAS and increased levels of other effectors of the MAPK pathway suggests a role for HRAS in the development of CRC, but further studies are needed to confirm this hypothesis [184,185]. Association between increased levels of HRAS and increased levels of other effectors of the MAPK pathway suggests a role for HRAS in the development of CRC, but further studies are needed to confirm this hypothesis [184,185].…”

Section: Ras Familymentioning

confidence: 99%

“…This resistance may be due to the EGFR-independent constitutive activation of the MAPK pathway; it has been suggested that HRAS and NRAS mutations may also confer this resistance [181]. Despite CRC tumors rarely show HRAS mutations [183], increased activity levels have been described, especially in women and in tumors with distant metastases [184]. Despite CRC tumors rarely show HRAS mutations [183], increased activity levels have been described, especially in women and in tumors with distant metastases [184].…”

Section: Ras Familymentioning

confidence: 99%

Molecular Biomarkers in Colorectal Carcinoma

2015

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Colorectal cancer is a tumor with increasing incidence which represents one of the first leading causes of death worldwide. Gene alterations described for colorectal cancer include genome instability (microsatellite and chromosomal instability), CpG islands methylator phenotype, microRNA, histone modification, protein biomarkers, gene mutations (RAS, BRAF, PI3K, TP53, PTEN) and polymorphisms (APC, CTNNB1, DCC). In this article, biomarkers with prognostic value commonly found in colorectal cancer will be reviewed.

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Interplay between oncogenic K-Ras and wild-type H-Ras in Caco2 cell transformation

Cited by 8 publications

References 23 publications

Lipoprotein-biomimetic nanostructure enables efficient targeting delivery of siRNA to Ras-activated glioblastoma cells via macropinocytosis

Lipoprotein-biomimetic nanostructure enables efficient targeting delivery of siRNA to Ras-activated glioblastoma cells via macropinocytosis

The role of wild type RAS isoforms in cancer

Molecular Biomarkers in Colorectal Carcinoma

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