Knockdown of Akt2 Expression by ShRNA Inhibits Proliferation, Enhances Apoptosis, and Increases Chemosensitivity to Paclitaxel in Human Colorectal Cancer Cells

Ding, Zhongyang; Xu, Fei; Gan, Li; Tang, Zhangfeng; Jiang, Pan‑Qiang; Wu, Haotian

doi:10.1007/s12013-014-0209-9

Cited by 15 publications

(11 citation statements)

References 20 publications

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“…It functions as an ATP-dependent drug efflux pump [29] and is known to decrease the intracellular concentration of chemotherapeutic agents [30]. MDR1 (P-gp) is deeply involved in tumor chemoresistance [31]. In this study, the results of the Rhodamine 123 efflux assay revealed that the function of P-gp was significantly inhibited in AA-only treatment group and in combination treatment groups.…”

Section: Discussionmentioning

confidence: 80%

Asiatic Acid (AA) Sensitizes Multidrug-Resistant Human Lung Adenocarcinoma A549/DDP Cells to Cisplatin (DDP) via Downregulation of P-Glycoprotein (MDR1) and Its Targets

Cheng¹,

Liao²,

Hu³

et al. 2018

Cell Physiol Biochem

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Background/Aims: P-glycoprotein (P-gp, i.e., MDR1) is associated with the phenotype of multidrug resistance (MDR) and causes chemotherapy failure in the management of cancers. Searching for effective MDR modulators and combining them with anticancer drugs is a promising strategy against MDR. Asiatic acid (AA), a natural triterpene isolated from the plant Centella asiatica, may have an antitumor activity. The present study assessed the reversing effect of AA on MDR and possible molecular mechanisms of AA action in MDR1-overexpressing cisplatin (DDP)-resistant lung cancer cells, A549/DDP. Methods: Human lung adenocarcinoma A549/DDP cells were either exposed to different concentrations of AA or treated with DDP, and their viability was measured by the MTT assay. A Rhodamine 123 efflux assay, immunofluorescent staining, ATPase assay, reverse-transcription PCR (RT-PCR), and western blot analysis were conducted to elucidate the mechanisms of action of AA on MDR. Results: Our results showed that AA significantly enhanced the cytotoxicity of DDP toward A549/DDP cells but not its parental A549 cells. Furthermore, AA strongly inhibited P-gp expression by blocking MDR1 gene transcription and increased the intracellular accumulation of the P-gp substrate Rhodamine 123 in A549/DDP cells. Nuclear factor (NF)-kB (p65) activity, IkB degradation, and NF-kB/p65 nuclear translocation were markedly inhibited by pretreatment with AA. Additionally, AA inhibited the MAPK–ERK pathway, as indicated by decreased phosphorylation of ERK1 and -2, AKT, p38, and JNK, thus resulting in reduced activity of the Y-box binding protein 1 (YB1) via blockage of its nuclear translocation. Conclusions: AA reversed P-gp-mediated MDR by inhibition of P-gp expression. This effect was likely related to downregulation of YB1, and this effect was mediated by the NF-kB and MAPK–ERK pathways. AA may be useful as an MDR reversal agent for combination therapy in clinical trials.

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Section: Discussionmentioning

confidence: 80%

Asiatic Acid (AA) Sensitizes Multidrug-Resistant Human Lung Adenocarcinoma A549/DDP Cells to Cisplatin (DDP) via Downregulation of P-Glycoprotein (MDR1) and Its Targets

Cheng¹,

Liao²,

Hu³

et al. 2018

Cell Physiol Biochem

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“…CDK9 inhibition enhanced p53 level and consequently led to increased apoptosis in cervical cancer cells. Recent findings also have shown that knockdown of AKT2 suppressed viability with enhanced apoptosis in glioblastoma, colorectal cancer, and cervical cancer (23,36,37). Further study shows that CDK9 knockdown also inhibits AKT2 expression.…”

Section: Discussionmentioning

confidence: 94%

Cyclin‐dependent kinase 9 promotes cervical cancer development via AKT2/p53 pathway

Fang

et al. 2018

IUBMB Life

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Aberrant activation of cyclin‐dependent kinase 9 (CDK9) is widespread in human cancers. However, the underlying mechanisms of CDK9 activation and the therapeutic potential of CDK9 inhibition in cervical cancer remain largely unknown. Here, we report that CDK9 is gradually upregulated during cervical lesion progression and regulated by HPV16 E6. CDK9 levels are highly correlated with FIGO stage, pathological grade, deep‐stromal invasion, tumor size, and lymph nodes metastasis. Knockdown of CDK9 by specific siRNA inhibits cervical cancer cell proliferation in vitro, as well as tumorigenesis in vivo. CDK9 inhibition causes a significant decreased AKT2 and increased p53 protein expression revealing novel CDK9‐regulatory mechanisms. Overexpression of AKT2 rescued the suppressive effects caused by CDK9 knockdown, suggesting that AKT2 induction is essential for CDK9‐induced transformation. Moreover, CDK9 expression was positively correlated with AKT2 and negatively correlated with p53 in cervical cancer tissues with HPV16 infection. Our findings demonstrate for the first time that CDK9 acts as a proto‐oncogene in cervical cancer, modulating cell proliferation and apoptosis through AKT2/p53 pathway. Therefore, our data provide novel mechanistic insights into the role of CDK9 in cervical cancer development. © 2018 IUBMB Life, 71(3):347–356, 2019

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“…In fact, knockdown © 1996-2016 of Akt2 decreased the expression of MDR1 and MRP1 protein in HCT116 human colorectal cancer cells (52) and the expression of MRP1 protein in U87 glioma cells (54), sensitizing these cells to paclitaxel and VM-26 (teniposide), respectively. This suggests that overexpression of MDR1 and MRP1 is via an Akt2dependent mechanism and decreased Akt2 signaling may reduce the efflux of these drugs through these ABC transporters via downregulation of MDR1 and MRP1 (52,54). Moreover, inhibition of Akt2 expression in A549 lung cancer cells resulted in significant inhibition of cell growth, proliferation, and invasion, and this was accompanied by reduced nucleophosmin/B23 protein (55).…”

Section: Akt2 Isoformmentioning

confidence: 99%

“…Akt2 confers resistance to chemotherapeutic drugs such as paclitaxel (52), doxorubicin (49), cisplatin (49), and gemcitabine (53). In fact, knockdown © 1996-2016 of Akt2 decreased the expression of MDR1 and MRP1 protein in HCT116 human colorectal cancer cells (52) and the expression of MRP1 protein in U87 glioma cells (54), sensitizing these cells to paclitaxel and VM-26 (teniposide), respectively. This suggests that overexpression of MDR1 and MRP1 is via an Akt2dependent mechanism and decreased Akt2 signaling may reduce the efflux of these drugs through these ABC transporters via downregulation of MDR1 and MRP1 (52,54).…”

Section: Akt2 Isoformmentioning

confidence: 99%

Emerging therapeutics for targeting Akt in cancer

Basu¹

2016

Front Biosci

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The ultimate goal of cancer therapeutic research is to develop effective, targeted therapeutics that exploit the vulnerabilities of cancer cells. The three isoforms of Akt, also known as protein kinase B (PKB), are important mediators of various pathways that transmit mitogenic signals from the cell's exterior to the effector proteins of the cell's interior. Due to Akt\\\\\\\'s importance in cell functions such as growth, proliferation and cell survival, many cancer cells rely on this pathway to aid in their survival. This dependence can lead to chemoresistance and selection of more adapted populations of cancer cells. Thus, it is important to understand the functional significance of isoform specificity and its relation to chemoresistance. In this review, we have summarized recent studies on Akt isoform specific regulation as well as each isoform's role in chemoresistance, emphasizing their potential as targets for cancer therapy. We have also condensed ongoing clinical studies involving various types of Akt inhibitors while highlighting the type of study, rationale and co-therapies involved in identifying Akt isoforms as promising therapeutic targets.

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Knockdown of Akt2 Expression by ShRNA Inhibits Proliferation, Enhances Apoptosis, and Increases Chemosensitivity to Paclitaxel in Human Colorectal Cancer Cells

Cited by 15 publications

References 20 publications

Asiatic Acid (AA) Sensitizes Multidrug-Resistant Human Lung Adenocarcinoma A549/DDP Cells to Cisplatin (DDP) via Downregulation of P-Glycoprotein (MDR1) and Its Targets

Asiatic Acid (AA) Sensitizes Multidrug-Resistant Human Lung Adenocarcinoma A549/DDP Cells to Cisplatin (DDP) via Downregulation of P-Glycoprotein (MDR1) and Its Targets

Cyclin‐dependent kinase 9 promotes cervical cancer development via AKT2/p53 pathway

Emerging therapeutics for targeting Akt in cancer

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