CDK5 is essential for TGF-β1-induced epithelial-mesenchymal transition and breast cancer progression

Liang, Qian; Li, Lili; Zhang, Jianchao; Yang, Lei; Wang, Liping; Liu, Dong-Xu; Feng, Jianxun; Hou, Pingfu; Yao, Ruosi; Huang, Baiqu; Lü, Jun

doi:10.1038/srep02932

Cited by 111 publications

(117 citation statements)

References 54 publications

(83 reference statements)

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“…It has also been documented that different CDKs may contribute specifically to different tumor types in humans (17,18). CDK5, an atypical CDK that was previously considered to function in processes unrelated to cell-cycle regulation, has been shown to play a fundamental role in several kinds of carcinomas including breast, lung, prostate, multiple myeloma, and pancreatic cancers (39)(40)(41)(42)(43). However, the potential role of CDK5 in gastric cancer has never been reported.…”

Section: Discussionmentioning

confidence: 99%

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Cyclin-Dependent Kinase 5 Decreases in Gastric Cancer and Its Nuclear Accumulation Suppresses Gastric Tumorigenesis

Cao

Zhou

Zhang

et al. 2015

Clinical Cancer Research

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Purpose: As a cyclin-independent atypical CDK, the role of CDK5 in regulating cell proliferation in gastric cancer remains unknown.Experimental Design: Expression of CDK5 in gastric tumor and paired adjacent noncancerous tissues from 437 patients was measured by Western blotting, immunohistochemistry, and realtime PCR. The subcellular translocation of CDK5 was monitored during gastric cancer cell proliferation. The role of nuclear CDK5 in gastric cancer tumorigenic proliferation and ex vivo xenografts was explored. Furthermore, by screening for compounds in the PubChem database that disrupt CDK5 association with its nuclear export facilitator, we identified a small molecular (NS-0011) that inhibits gastric cancer cell growth.Results: CDK5 level was significantly decreased in the majority of gastric tumor tissues, and the reduction of CDK5 correlated with the severity of gastric cancer based on tumor and lymph node metastasis and patient 5-year fatality rate. Nuclear localization of CDK5 was found to be significantly decreased in tumor tissues and gastric cancer cell lines, whereas exogenously expression of nucleus-targeted CDK5 inhibited the proliferation and xenograft implantation of gastric cancer cells. Treatment with the small molecule NS-0011, which increases CDK5 accumulation in the nucleus, suppressed both cancer cell proliferation and xenograft tumorigenesis.Conclusions: Our results suggest that low CDK5 expression is associated with poor overall survival in patients with gastric cancer, and nuclear accumulation of CDK5 inhibits the proliferation and tumorigenicity of human gastric cancer cells.

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Section: Discussionmentioning

confidence: 99%

“…This may suggest that CDK5 in fact plays an inhibitory role in gastric tumorigenesis. The kinase activity of CDK5 has been thought to mediate carcinogensis of certain nongastric cancer types (39)(40)(41)(42)(43). Our previous studies indicated that nuclear CDK5 can function as a cell-cycle suppressor in the nervous system (28)(29)(30).…”

Section: Discussionmentioning

confidence: 99%

Cyclin-Dependent Kinase 5 Decreases in Gastric Cancer and Its Nuclear Accumulation Suppresses Gastric Tumorigenesis

Cao

Zhou

Zhang

et al. 2015

Clinical Cancer Research

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“…Thus, Cdk5-Nrf2 signaling seems to be ubiquitous, in view of its occurrence in neurons besides astrocytes. Nrf2 is also elevated in cancer cells, 13,42,43 hence it is tempting to speculate that Cdk5 -which contributes to cancer progression 44 -would sustain Nrf2-mediated antioxidant activity and survival of rapidly proliferating cells.…”

Section: Discussionmentioning

confidence: 99%

Astrocyte NMDA receptors' activity sustains neuronal survival through a Cdk5–Nrf2 pathway

et al. 2015

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Neurotransmission unavoidably increases mitochondrial reactive oxygen species. However, the intrinsic antioxidant defense of neurons is weak and hence the mechanism whereby these cells are physiologically protected against oxidative damage is unknown. Here we found that the antioxidant defense of neurons is repressed owing to the continuous protein destabilization of the master antioxidant transcriptional activator, nuclear factor-erythroid 2-related factor-2 (Nrf2). By contrast, Nrf2 is highly stable in neighbor astrocytes explaining their robust antioxidant defense and resistance against oxidative stress. We also show that subtle and persistent stimulation of N-methyl-D-aspartate receptors (NMDAR) in astrocytes, through a mechanism not requiring extracellular Ca 2+ influx, upregulates a signal transduction pathway involving phospholipase C-mediated endoplasmic reticulum release of Ca 2+ and protein kinase Cδ activation. Active protein kinase Cδ promotes, by phosphorylation, the stabilization of p35, a cyclin-dependent kinase-5 (Cdk5) cofactor. Active p35/Cdk5 complex in the cytosol phosphorylates Nrf2 at Thr 395 , Ser 433 and Thr 439 that is sufficient to promote Nrf2 translocation to the nucleus and induce the expression of antioxidant genes. Furthermore, this Cdk5-Nrf2 transduction pathway boosts glutathione metabolism in astrocytes efficiently protecting closely spaced neurons against oxidative damage. Thus, intercellular communication through NMDAR couples neurotransmission with neuronal survival.

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“…CDK5 has previously been shown to be overexpressed in patients with breast cancer, pancreatic cancer, medullary thyroid carcinoma, prostate cancer, lung cancer, and glioblastoma, 81,82 and is an autophagy inducer in neurons in in vitro models of Parkinson disease. 83 We found that stratification of expression of our gene set by the alteration status of molecular changes previously implicated in breast cancer (Table S5) revealed increased mRNA levels of ATG5 and FOXO3 in KRAS-amplified BRCA patients.…”

Section: Clear Cell Renal Carcinomamentioning

confidence: 99%

Cross-cancer profiling of molecular alterations within the human autophagy interaction network

et al. 2015

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Aberrant activation or disruption of autophagy promotes tumorigenesis in various preclinical models of cancer, but whether the autophagy pathway is a target for recurrent molecular alteration in human cancer patient samples is unknown. To address this outstanding question, we surveyed 211 human autophagy-associated genes for tumorrelated alterations to DNA sequence and RNA expression levels and examined their association with patient survival outcomes in multiple cancer types with sequence data from The Cancer Genome Atlas consortium. We found 3 (RB1CC1/FIP200, ULK4, WDR45/WIPI4) and one (ATG7) core autophagy genes to be under positive selection for somatic mutations in endometrial carcinoma and clear cell renal carcinoma, respectively, while 29 autophagy regulators and pathway interactors, including previously identified KEAP1, NFE2L2, and MTOR, were significantly mutated in 6 of the 11 cancer types examined. Gene expression analyses revealed that GABARAPL1 and MAP1LC3C/LC3C transcripts were less abundant in breast cancer and non-small cell lung cancers than in matched normal tissue controls; ATG4D transcripts were increased in lung squamous cell carcinoma, as were ATG16L2 transcripts in kidney cancer. Unsupervised clustering of autophagy-associated mRNA levels in tumors stratified patient overall survival in 3 of 9 cancer types (acute myeloid leukemia, clear cell renal carcinoma, and head and neck cancer). These analyses provide the first comprehensive resource of recurrently altered autophagy-associated genes in human tumors, and highlight cancer types and subtypes where perturbed autophagy may be relevant to patient overall survival.

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CDK5 is essential for TGF-β1-induced epithelial-mesenchymal transition and breast cancer progression

Cited by 111 publications

References 54 publications

Cyclin-Dependent Kinase 5 Decreases in Gastric Cancer and Its Nuclear Accumulation Suppresses Gastric Tumorigenesis

Cyclin-Dependent Kinase 5 Decreases in Gastric Cancer and Its Nuclear Accumulation Suppresses Gastric Tumorigenesis

Astrocyte NMDA receptors' activity sustains neuronal survival through a Cdk5–Nrf2 pathway

Cross-cancer profiling of molecular alterations within the human autophagy interaction network

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