Functional specificity of Akt isoforms in cancer progression

2011 ◽  
Vol 2 (1-2) ◽  
pp. 1-11 ◽  
Author(s):  
Anne-Marie Fortier ◽  
Eric Asselin ◽  
Monique Cadrin
Keyword(s):  
Tumor Growth ◽  
Cancer Cell ◽  
Cancer Progression ◽  
Cell Invasion ◽  
Human Cancer ◽  
Cancer Cell Invasion ◽  
Akt Inhibitor ◽  
Akt Isoforms ◽  
Specific Localization ◽  
Inhibitor Drug

AbstractAkt/PKB kinases are central mediators of cell homeostasis. There are three highly homologous Akt isoforms, Akt1/PKBα, Akt2/PKBβ and Akt3/PKBγ. Hyperactivation of Akt signaling is a key node in the progression of a variety of human cancer, by modulating tumor growth, chemoresistance and cancer cell migration, invasion and metastasis. It is now clear that, to understand the mechanisms on how Akt affects specific cancer cells, it is necessary to consider the relative importance of each of the three Akt isoforms in the altered cells. Akt1 is involved in tumor growth, cancer cell invasion and chemoresistance and is the predominant altered isoform found in various carcinomas. Akt2 is related to cancer cell invasion, metastasis and survival more than tumor induction. Most of the Akt2 alterations are observed in breast, ovarian, pancreatic and colorectal carcinomas. As Akt3 expression is limited to some tissues, its implication in tumor growth and resistance to drugs mostly occurs in melanomas, gliomas and some breast carcinomas. To explain how Akt isoforms can play different or even opposed roles, three mechanisms have been proposed: tissue-specificity expression/activation of Akt isoforms, distinct effect on same substrate as well as specific localization through the cyto-skeleton network. It is becoming clear that to develop an effective anticancer Akt inhibitor drug, it is necessary to target the specific Akt isoform which promotes the progression of the specific tumor.

Synergistic inhibition of lung cancer cell invasion, tumor growth and angiogenesis using aptamer-siRNA chimeras

Biomaterials ◽  
2014 ◽  
Vol 35 (9) ◽  
pp. 2905-2914 ◽  
Author(s):  
Wei-Yun Lai ◽  
Wei-Ya Wang ◽  
Yi-Chung Chang ◽  
Cheng-Ju Chang ◽  
Pan-Chyr Yang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tumor Growth ◽  
Cancer Cell ◽  
Cell Invasion ◽  
Cancer Cell Invasion ◽  
Lung Cancer Cell ◽  
Synergistic Inhibition

scholarly journals TP53 drives invasion through expression of its Δ133p53β variant

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Gilles Gadea ◽  
Nikola Arsic ◽  
Kenneth Fernandes ◽  
Alexandra Diot ◽  
Sébastien M Joruiz ◽  
...  
Keyword(s):  
Cancer Cell ◽  
Cancer Progression ◽  
Cell Invasion ◽  
Tp53 Mutation ◽  
P53 Protein ◽  
Clinical Analysis ◽  
Breast Cancer Patients ◽  
Cancer Cell Invasion ◽  
Mutation Status ◽  
Risk Of Cancer

TP53 is conventionally thought to prevent cancer formation and progression to metastasis, while mutant TP53 has transforming activities. However, in the clinic, TP53 mutation status does not accurately predict cancer progression. Here we report, based on clinical analysis corroborated with experimental data, that the p53 isoform Δ133p53β promotes cancer cell invasion, regardless of TP53 mutation status. Δ133p53β increases risk of cancer recurrence and death in breast cancer patients. Furthermore Δ133p53β is critical to define invasiveness in a panel of breast and colon cell lines, expressing WT or mutant TP53. Endogenous mutant Δ133p53β depletion prevents invasiveness without affecting mutant full-length p53 protein expression. Mechanistically WT and mutant Δ133p53β induces EMT. Our findings provide explanations to 2 long-lasting and important clinical conundrums: how WT TP53 can promote cancer cell invasion and reciprocally why mutant TP53 gene does not systematically induce cancer progression.

scholarly journals Localization of KRAS downstream target ARL4C to invasive pseudopods accelerates pancreatic cancer cell invasion

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Akikazu Harada ◽  
Shinji Matsumoto ◽  
Yoshiaki Yasumizu ◽  
Toshiyuki Akama ◽  
Hidetoshi Eguchi ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Patients ◽  
Cancer Cell ◽  
Cell Invasion ◽  
Cancer Cell Invasion ◽  
Interacting Protein ◽  
Downstream Target ◽  
Downstream Effector ◽  
Pancreatic Cancer Cells ◽  
Specific Localization

Pancreatic cancer has a high mortality rate due to metastasis. Whereas KRAS is mutated in most pancreatic cancer patients, controlling KRAS or its downstream effectors has not been succeeded clinically. ARL4C is a small G protein whose expression is induced by the Wnt and EGF-RAS pathways. In the present study, we found that ARL4C is frequently overexpressed in pancreatic cancer patients and showed that its localization to invasive pseudopods is required for cancer cell invasion. IQGAP1 was identified as a novel interacting protein for ARL4C. ARL4C recruited IQGAP1 and its downstream effector, MMP14, to invasive pseudopods. Specific localization of ARL4C, IQGAP1, and MMP14 was the active site of invasion, which induced degradation of the extracellular matrix. Moreover, subcutaneously injected antisense oligonucleotide against ARL4C into tumor-bearing mice suppressed metastasis of pancreatic cancer. These results suggest that ARL4C-IQGAP1-MMP14 signaling is activated at invasive pseudopods of pancreatic cancer cells.

scholarly journals Cancer Invasion: Patterns and Mechanisms

Acta Naturae ◽  
2015 ◽  
Vol 7 (2) ◽  
pp. 17-28 ◽  
Author(s):  
N. V. Krakhmal ◽  
M. V. Zavyalova ◽  
E. V. Denisov ◽  
S. V. Vtorushin ◽  
V. M. Perelmuter
Keyword(s):  
Cell Migration ◽  
Tumor Cells ◽  
Cancer Cell ◽  
Cancer Progression ◽  
Cell Invasion ◽  
Cancer Invasion ◽  
Collective Cell Migration ◽  
Cancer Cell Migration ◽  
Cancer Cell Invasion ◽  
Invasion Patterns

Cancer invasion and the ability of malignant tumor cells for directed migration and metastasis have remained a focus of research for many years. Numerous studies have confirmed the existence of two main patterns of cancer cell invasion: collective cell migration and individual cell migration, by which tumor cells overcome barriers of the extracellular matrix and spread into surrounding tissues. Each pattern of cell migration displays specific morphological features and the biochemical/molecular genetic mechanisms underlying cell migration. Two types of migrating tumor cells, mesenchymal (fibroblast-like) and amoeboid, are observed in each pattern of cancer cell invasion. This review describes the key differences between the variants of cancer cell migration, the role of epithelial-mesenchymal, collective-amoeboid, mesenchymal-amoeboid, and amoeboid-mesenchymal transitions, as well as the significance of different tumor factors and stromal molecules in tumor invasion. The data and facts collected are essential to the understanding of how the patterns of cancer cell invasion are related to cancer progression and therapy efficacy. Convincing evidence is provided that morphological manifestations of the invasion patterns are characterized by a variety of tissue (tumor) structures. The results of our own studies are presented to show the association of breast cancer progression with intratumoral morphological heterogeneity, which most likely reflects the types of cancer cell migration and results from different activities of cell adhesion molecules in tumor cells of distinct morphological structures.

scholarly journals The Identification of Small Molecule Inhibitors That Reduce Invasion and Metastasis of Aggressive Cancers

2021 ◽  
Vol 22 (4) ◽  
pp. 1688
Author(s):  
Arjanneke F. van de Merbel ◽  
Onno van Hooij ◽  
Geertje van der Horst ◽  
Cindy C. M. van Rijt-van de Westerlo ◽  
Maaike H. van der Mark ◽  
...  
Keyword(s):  
Cancer Cell ◽  
Cell Invasion ◽  
Human Cancer ◽  
Intraperitoneal Administration ◽  
Human Prostate ◽  
Cancer Cell Invasion ◽  
Invasive Phenotype ◽  
Mesenchymal Phenotype ◽  
Epithelial Phenotype ◽  
E Cadherin

Transformed epithelial cells can activate programs of epithelial plasticity and switch from a sessile, epithelial phenotype to a motile, mesenchymal phenotype. This process is linked to the acquisition of an invasive phenotype and the formation of distant metastases. The development of compounds that block the acquisition of an invasive phenotype or revert the invasive mesenchymal phenotype into a more differentiated epithelial phenotype represent a promising anticancer strategy. In a high-throughput assay based on E-cadherin (re)induction and the inhibition of tumor cell invasion, 44,475 low molecular weight (LMW) compounds were screened. The screening resulted in the identification of candidate compounds from the PROAM02 class. Selected LMW compounds activated E-cadherin promoter activity and inhibited cancer cell invasion in multiple metastatic human cancer cell lines. The intraperitoneal administration of selected LMW compounds reduced the tumor burden in human prostate and breast cancer in vivo mouse models. Moreover, selected LMW compounds decreased the intra-bone growth of xenografted human prostate cancer cells. This study describes the identification of the PROAM02 class of small molecules that can be exploited to reduce cancer cell invasion and metastases. Further clinical evaluation of selected candidate inhibitors is warranted to address their safety, bioavailability and antitumor efficacy in the management of patients with aggressive cancers.

CSE1L modulates Ras-induced cancer cell invasion: correlation of K-Ras mutation and CSE1L expression in colorectal cancer progression

2013 ◽  
Vol 206 (3) ◽  
pp. 418-427 ◽  
Author(s):  
Ming-Chung Jiang ◽  
Chung-Min Yeh ◽  
Cheng-Jeng Tai ◽  
Hung-Chang Chen ◽  
Shu-Hui Lin ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cell ◽  
Cancer Progression ◽  
Cell Invasion ◽  
Cancer Cell Invasion ◽  
Ras Mutation ◽  
Colorectal Cancer Progression
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