Dampened PI3K/AKT signaling contributes to cancer resistance of the naked mole rat (original) (raw)
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BMC Genomics
Background: Spalax, the blind mole rat, developed an extraordinary cancer resistance during 40 million years of evolution in a subterranean, hypoxic, thus DNA damaging, habitat. In 50 years of Spalax research, no spontaneous cancer development has been observed. The mechanisms underlying this resistance are still not clarified. We investigated the genetic difference between Spalax and mice that might enable the Spalax relative resistance to cancer development. We compared Spalax and mice responses to a treatment with the carcinogen 3-Methylcholantrene, as a model to assess Spalax' cancer-resistance. Results: We compared RNA-Seq data of untreated Spalax to Spalax with a tumor and identified a high number of differentially expressed genes. We filtered these genes by their expression in tolerant Spalax that resisted the 3MCA, and in mice, and found 25 genes with a consistent expression pattern in the samples susceptible to cancer among species. Contrasting the expressed genes in Spalax with benign granulomas to those in Spalax with malignant fibrosarcomas elucidated significant differences in several pathways, mainly related to the extracellular matrix and the immune system. We found a central cluster of ECM genes that differ greatly between conditions. Further analysis of these genes revealed potential microRNA targets. We also found higher levels of gene expression of some DNA repair pathways in Spalax than in other murines, like the majority of Fanconi Anemia pathway. Conclusion: The comparison of the treated with the untreated tissue revealed a regulatory complex that might give an answer how Spalax is able to restrict the tumor growth. By remodeling the extracellular matrix, the possible growth is limited, and the proliferation of cancer cells was potentially prevented. We hypothesize that this regulatory cluster plays a major role in the cancer resistance of Spalax. Furthermore, we identified 25 additional candidate genes that showed a distinct expression pattern in untreated or tolerant Spalax compared to animals that developed a developed either a benign or malignant tumor. While further study is necessary, we believe that these genes may serve as candidate markers in cancer detection.
Cancer Research, 2013
The selective pressures leading to cancers with mutations in both KRAS and PIK3CA are unclear. Here, we show that somatic cell knockin of both KRAS G12V and oncogenic PIK3CA mutations in human breast epithelial cells results in cooperative activation of the phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways in vitro, and leads to tumor formation in immunocompromised mice. Xenografts from double-knockin cells retain single copies of mutant KRAS and PIK3CA, suggesting that tumor formation does not require increased copy number of either oncogene, and these results were also observed in human colorectal cancer specimens. Mechanistically, the cooperativity between mutant KRAS and PIK3CA is mediated in part by Ras/p110α binding, as inactivating point mutations within the Ras-binding domain of PIK3CA significantly abates pathway signaling. In addition, Pdk1 activation of the downstream effector p90RSK is also increased by the combined presence of mutant ...
Mouse Models to Decipher the PI3K Signaling Network in Human Cancer
Current Molecular Medicine, 2009
Deregulation of the PI3K pathway is common in human cancer. The basic players in this pathway are the kinases PI3K and AKT and the phosphatase PTEN. This review will summarize some of the key animal models that have helped us understand this signaling network and its contribution to tumorigenesis. Recently, great advances in cancer mouse models have been achieved [1]. While germline deletion often affects the development of the organism and can result in embryonic lethality, conditional knockout mouse models offer the possibility of inducing gene deletion in the adult organism. Another useful strategy involves the inactivation of enzyme function by introducing small mutations in the gene sequence, thereby maintaining the protein in an inactivated state and mimicking protein inhibition with drugs. Combining tissue-specific expression of PI3K and AKT with a secondary oncogenic event, for example, leads to the development of specific tumors. Such models are more accurate for growth studies of human tumors than those involving xenograft tumors, due to the interconnection of the tumors with blood vessels. These studies will improve the pharmacological analysis of drug candidates. With the discovery of oncogenic mutations in members of the PI3K pathway, mouse lines harboring these mutations are being developed in order to imitate the molecular features of a human tumor. Using these models for drug testing may enable more accurate prediction of the effects that a specific drug will have on a patient.
Molecular cell, 2011
Mutations in both RAS and the PTEN/PIK3CA/AKT signaling module are found in the same human tumors. PIK3CA and AKT are downstream effectors of RAS, and the selective advantage conferred by mutation of two genes in the same pathway is unclear. Based on a comparative molecular analysis, we show that activated PIK3CA/AKT is a weaker inducer of senescence than is activated RAS. Moreover, concurrent activation of RAS and PIK3CA/AKT impairs RAS-induced senescence. In vivo, bypass of RAS-induced senescence by activated PIK3CA/AKT correlates with accelerated tumorigenesis. Thus, not all oncogenes are equally potent inducers of senescence, and, paradoxically, a weak inducer of senescence (PIK3CA/AKT) can be dominant over a strong inducer of senescence (RAS). For tumor growth, one selective advantage of concurrent mutation of RAS and PTEN/PIK3CA/AKT is suppression of RAS-induced senescence. Evidence is presented that this new understanding can be exploited in rational development and targeted ...
Journal of Biotechnology, 2010
Mouse functional genomics is largely used to investigate relevant aspects of mammalian physiology and pathology. To which degree mouse models may offer accurate representations of molecular events underlining human diseases such as cancer is not yet fully established. Herein we compare gene expression signatures between a set of human cancer cell lines (NCI-60 cell collection) and a mouse cellular model of oncogenic K-ras dependent transformation in order to identify their closeness at the transcriptional level. The results of our integrative and comparative analysis show that in both species as compared to normal cells or tissues the transformation process involves the activation of a transcriptional response. Furthermore, the cellular mouse model of K-ras dependent transformation has a good degree of similarity with several human cancer cell lines and in particular with cell lines containing oncogenic Ras mutations. Moreover both species have similar genetic signatures that are associated to the same altered cellular pathways (e.g. Spliceosome and Proteasome) or to deregulation of the same genes (e.g. cyclin D1, AHSA1 and HNRNPD) detected in the comparison between cancer cells versus normal cells or tissues. In summary, we report one of the first indepth analysis of global gene expression profiles of a K-ras dependent mouse cell model of transformation and a large collection of human cancer cells as compared to their normal counterparts. Taken together our findings show a strong correlation in the transcriptional and pathway alteration responses between the two species, therefore validating the use of the mouse model as an appropriate tool to investigate human cancer, and indicating that the comparative analysis, as described here, offers a useful approach to identify cancer-specific gene signatures.
Biotechnology Advances, 2012
Mouse functional genomics is largely used to investigate relevant aspects of mammalian physiology and pathology. To which degree mouse models may offer accurate representations of molecular events underlining human diseases such as cancer is not yet fully established. Herein we compare gene expression signatures between a set of human cancer cell lines (NCI-60 cell collection) and a mouse cellular model of oncogenic K-ras dependent transformation in order to identify their closeness at the transcriptional level. The results of our integrative and comparative analysis show that in both species as compared to normal cells or tissues the transformation process involves the activation of a transcriptional response. Furthermore, the cellular mouse model of K-ras dependent transformation has a good degree of similarity with several human cancer cell lines and in particular with cell lines containing oncogenic Ras mutations. Moreover both species have similar genetic signatures that are associated to the same altered cellular pathways (e.g. Spliceosome and Proteasome) or to deregulation of the same genes (e.g. cyclin D1, AHSA1 and HNRNPD) detected in the comparison between cancer cells versus normal cells or tissues. In summary, we report one of the first indepth analysis of global gene expression profiles of a K-ras dependent mouse cell model of transformation and a large collection of human cancer cells as compared to their normal counterparts. Taken together our findings show a strong correlation in the transcriptional and pathway alteration responses between the two species, therefore validating the use of the mouse model as an appropriate tool to investigate human cancer, and indicating that the comparative analysis, as described here, offers a useful approach to identify cancer-specific gene signatures.
Cancer Research, 2013
The selective pressures leading to cancers with mutations in both KRAS and PIK3CA are unclear. Here, we show that somatic cell knockin of both KRAS G12V and oncogenic PIK3CA mutations in human breast epithelial cells results in cooperative activation of the phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways in vitro, and leads to tumor formation in immunocompromised mice. Xenografts from doubleknockin cells retain single copies of mutant KRAS and PIK3CA, suggesting that tumor formation does not require increased copy number of either oncogene, and these results were also observed in human colorectal cancer specimens. Mechanistically, the cooperativity between mutant KRAS and PIK3CA is mediated in part by Ras/ p110a binding, as inactivating point mutations within the Ras-binding domain of PIK3CA significantly abates pathway signaling. In addition, Pdk1 activation of the downstream effector p90RSK is also increased by the combined presence of mutant KRAS and PIK3CA. These results provide new insights into mutant KRAS function and its role in carcinogenesis. Cancer Res; 73(11); 3248-61. Ó2013 AACR.
Liver international : official journal of the International Association for the Study of the Liver, 2015
Activating mutations of PIK3CA occur in various tumor types, including human hepatocellular carcinoma. The mechanisms whereby PIK3CA contributes to hepatocarcinogenesis remain poorly understood. PIK3CA mutants H1047R or E545K were hydrodynamically transfected, either alone or in combination with NRasV12 or c-Met genes, in the mouse liver. Overexpression of H1047R or E545K alone was able to induce AKT/mTOR signaling in the mouse liver, leading to hepatic steatosis. However, none of the mice developed liver tumors over long term. In contrast, H1047R or E545K cooperated with NRasV12 or c-Met rapidly induce liver tumor formation in mice. At the molecular level, all the tumor nodules displayed activation of AKT/mTOR and Ras/MAPK cascades. Ablation of AKT2 significantly inhibited hepatic steatosis induced by H1047R or E545K and carcinogenesis induced by H1047R/c-Met or E545K/c-Met. Furthermore, tumorigenesis induced by H1047R/c-Met was abolished in conditional Raptor knockout mice. In con...
The Pathogenic Role of PI3K/AKT Pathway in Cancer Onset and Drug Resistance: An Updated Review
Cancers
The PI3K/AKT pathway is one of the most frequently over-activated intracellular pathways in several human cancers. This pathway, acting on different downstream target proteins, contributes to the carcinogenesis, proliferation, invasion, and metastasis of tumour cells. A multi-level impairment, involving mutation and genetic alteration, aberrant regulation of miRNAs sequences, and abnormal phosphorylation of cascade factors, has been found in multiple cancer types. The deregulation of this pathway counteracts common therapeutic strategies and contributes to multidrug resistance. In this review, we underline the involvement of this pathway in patho-physiological cell survival mechanisms, emphasizing its key role in the development of drug resistance. We also provide an overview of the potential inhibition strategies currently available.
Oncogene, 2002
Carcinogenesis by oncogenic Ras and Her-2 involves enhanced proliferation of epithelial cells in vivo. However, hyperproliferation induced by these oncogenes, or their downstream pathways in vitro has mainly been studied in cultured, fibroblastic cell lines. Here, we demonstrate that oncogenic Ha-Ras or constitutively active Her-2 cause increased proliferation and cyclin D1 upregulation in fully polarized, mammary epithelial cells (EpH4), if cultivated as organotypic structures in three-dimensional collagen/ matrigel matrices. Under standard culture conditions, however, these oncogenes failed to induce hyperproliferation. Using both specific low molecular weight inhibitors and Ras-effector -specific mutants, we dissected signaling pathways downstream of oncogenic Ras (PI3K, Mek1/ MAPK) with respect to (i) hyperproliferation in collagen gels and tumorigenesis in mice and (ii) epithelial/ mesenchymal transition (EMT). We show that the Rasactivated PI3K pathway is required to induce rapid tumor growth and enhanced proliferation of EpH4 cells in collagen gels, but fails to cause EMT in vitro and in vivo. On the other hand, Ras-dependent activation of the Mek1/ MAPK pathway in EpH4 cells (previously shown to cause EMT and metastasis) did not induce hyperproliferation in collagen gels and caused only slow tumor growth. Our data thus indicate that Ras-dependent signaling through the PI3K-and MAPK pathways fulfil distinct, but complementary functions during carcinogenesis.