PI3K/Akt/mTOR Signaling Pathway and the Biphasic Effect of Arsenic in Carcinogenesis

Chen, Qiao Yi; Costa, Max

doi:10.1124/mol.118.112268

Cited by 69 publications

(37 citation statements)

References 137 publications

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“…AKT, a serine/threonine-specific protein kinase, regulates cell proliferation and survival via phosphorylating and activating or inactivating downstream molecules. The results here are similar to previous finding that emphasizes the role of the alternative NF-κB pathway in cell proliferation, regulated by the AKT/mTOR signaling pathway [ 33 ]. In SPC-A1 lung cancer cells, cell proliferation is suppressed by the RelB-silencing.…”

Section: Discussionsupporting

confidence: 92%

RelB plays an oncogenic role and conveys chemo-resistance to DLD-1 colon cancer cells

et al. 2018

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BackgroundNuclear transcription factor kappa B (NF-κB) subunits exhibit crucial roles in tumorigenesis and chemo-sensitivity. Recent studies suggest that RelB, the key subunit of the alternative NF-κB pathway, plays a critical role in the progression of diverse human malignancies. However, the significance of RelB in colorectal cancer (CRC) remains unclear. Here, we systematically explored the functions of the alternative NF-κB subunit RelB in colon cancer cells and its underlying mechanism.MethodsStably transfected RelB-shRNA DLD-1 cells were established using Lipofectamine 2000. NF-κB DNA-binding capability was quantified using an ELISA-based NF-κB activity assay. Cell growth was monitored by an x-Celligence system. Cell proliferation was analyzed by a CCK-8 and a Brdu proliferation assay. Response to 5-FU was assessed by an x-Celligence system. Cell apoptosis and cell cycle was detected using flow cytometry analyses. Cell migration and invasion abilities were detected by an x-Celligence system, Transwell inserts, and wound-healing assays. RelB expression and its clinical significance were analyzed using the CRC tissue microarray. The expression of NF-κB signaling subunits, AKT/mTOR signaling molecules, cell cycle related proteins, MMP2, MMP9, and Integrin β-1 were measured by Western blotting analyses.ResultsThe RelB-silencing inhibited cell growth of DLD-1 cells. The RelB-silencing exerted the anti-proliferative by downregulation of AKT/mTOR signaling. The RelB-silencing caused G0–G1 cell cycle arrested likely due to decreasing the expression of Cyclin D1 and CDK4, concomitant with increased expression of p27Kip1. The RelB-silencing enhanced cytotoxic effect of 5-FU and induced cell accumulation in S-phase. The RelB-silencing impaired the migration and invasion potential of DLD-1 cells, which was related to downregulation of MMP2, MMP9, and Integrin β-1. Importantly, the RelB expression was correlated with depth of tumor invasion, lymph node metastasis, metastasis stage, and pTNM stage. High-RelB expression was significantly correlated with poor overall survival in CRC patients.ConclusionOur studies here provided evidence that RelB plays an oncogenic role and conveys chemo-resistance to 5-FU. RelB can be considered as an independent indicator of prognosis in CRC.

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Section: Discussionsupporting

confidence: 92%

RelB plays an oncogenic role and conveys chemo-resistance to DLD-1 colon cancer cells

et al. 2018

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“…Although inhibitory or activating effects of arsenite on mTOR have been reported (Chen & Costa, 2018), we found in MCF-7 breast cancer cells that arsenite stress activated mTORC1, as monitored by the phosphorylation of p70-S6K at threonine 389 (p70-S6K-T389) and 4E-BP1 at threonine 37/46 (4E-BP1-pT37/46) (Fig 1A and B). Note that the 4E-BP1 protein is present in three forms with different phosphorylation states.…”

Section: Resultsmentioning

confidence: 75%

“…Already after 5 min, arsenite acutely enhanced phosphorylation of the AGC kinase Akt at T308 (Akt-T308), which remained high throughout the time course. Class I PI3Ks have been proposed to mediate Akt activation upon stress (Chen & Costa, 2018). In agreement, stress-induced Akt-T308 phosphorylation was prevented by the pan-PI3K inhibitor wortmannin (Arcaro & Wymann, 1993) and the class I PI3K-specific inhibitor GDC-0941 (Folkes et al, 2008) (Fig 2A and B).…”

Section: Resultsmentioning

confidence: 99%

The PI3K and MAPK/p38 pathways control stress granule assembly in a hierarchical manner

et al. 2019

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All cells and organisms exhibit stress-coping mechanisms to ensure survival. Cytoplasmic protein-RNA assemblies termed stress granules are increasingly recognized to promote cellular survival under stress. Thus, they might represent tumor vulnerabilities that are currently poorly explored. The translation-inhibitory eIF2α kinases are established as main drivers of stress granule assembly. Using a systems approach, we identify the translation enhancers PI3K and MAPK/p38 as pro-stress-granule-kinases. They act through the metabolic master regulator mammalian target of rapamycin complex 1 (mTORC1) to promote stress granule assembly. When highly active, PI3K is the main driver of stress granules; however, the impact of p38 becomes apparent as PI3K activity declines. PI3K and p38 thus act in a hierarchical manner to drive mTORC1 activity and stress granule assembly. Of note, this signaling hierarchy is also present in human breast cancer tissue. Importantly, only the recognition of the PI3K-p38 hierarchy under stress enabled the discovery of p38’s role in stress granule formation. In summary, we assign a new pro-survival function to the key oncogenic kinases PI3K and p38, as they hierarchically promote stress granule formation.

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“…Given the information from GEO database and several pairs of sense and antisense related studies, 34 , 37 we speculated that ADAMTS9-AS2 might play a role in bladder tumor by regulating the ADAMTS9 expression. Besides, ADAMTS9 functions as a critical player in the process of AKT /mTOR signaling pathway as evidenced by Chen et al 33 , 39 Noticeably, the activation of the PI3K / AKT /mTOR signaling pathway is widely recognized as an essential part of regulatory mechanism in tumors including bladder cancer. 40 , 42 As previously mentioned, ADAMTS9-AS2 expression was correspondent with ADAMTS9 .…”

Section: Discussionmentioning

confidence: 99%

<p>Long Noncoding RNA <em>ADAMTS9-AS2</em> Inhibits the Proliferation, Migration, and Invasion in Bladder Tumor Cells</p>

Zhang

Jia

Zhang

et al. 2020

OTT

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Background: Bladder tumor is the fifth most prevalent tumor in men, yet its pathogenesis remains to be fully identified. Albeit a host of long noncoding RNAs (lncRNA) are emerging as new players involved in bladder tumor, the functions of many lncRNAs are still enigmatic. Reports on the deluge of studies on lncRNA ADAMTS9-AS2 have been convincingly associated with various tumors, but without mention of its roles in bladder tumor. Therefore, the roles of ADAMTS9-AS2 in bladder tumor cells were explored in our study. Materials and Methods: Quantitative real-time PCR assays and bioinformatic tools were applied in bladder tumor cells to identify the ADAMTS9-AS2 and ADAMTS9 expression. Western blot assays were performed to obtain the protein levels of bladder tumor related key molecules. CCK8, clonogenic assay, scratch wound healing, and transwell assays were separately applied to identify the functional roles of ADAMTS9-AS2 on proliferation, migration, and invasion in bladder tumor cells. Results: First, ADAMTS9-AS2 downregulation in bladder tumor cells was identified. Overexpression and knockdown experiments showed that ADAMTS9-AS2 expression was positively related to ADAMTS9, which is in accordance with the results from GEO database. Second, ADAMTS9-AS2 contributed to the inhibition of proliferation, migration, and invasion in bladder tumor cells. Third, ADAMTS9-AS2 was linked with PI3K/AKT/mTOR pathway related-molecules, several key autophagy, and apoptotic proteins. Conclusion: Conjointly, our findings suggested that ADAMTS9-AS2 might function as a tumor suppressor to restrain the proliferation, migration, and invasion in bladder tumor cells. The potential mechanism of ADAMTS9-AS2 related to PI3K/AKT/mTOR signal pathway was further identified. Of note, we found that ADAMTS9-AS2 has a significant effect on several key autophagy and apoptotic proteins. Therefore, these observations will provide supportive evidence to ADAMTS9-AS2 as a potential biomarker in patients with bladder tumor.

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PI3K/Akt/mTOR Signaling Pathway and the Biphasic Effect of Arsenic in Carcinogenesis

Cited by 69 publications

References 137 publications

RelB plays an oncogenic role and conveys chemo-resistance to DLD-1 colon cancer cells

RelB plays an oncogenic role and conveys chemo-resistance to DLD-1 colon cancer cells

The PI3K and MAPK/p38 pathways control stress granule assembly in a hierarchical manner

<p>Long Noncoding RNA <em>ADAMTS9-AS2</em> Inhibits the Proliferation, Migration, and Invasion in Bladder Tumor Cells</p>

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