Role of EIF5A2, a downstream target of Akt, in promoting melanoma cell invasion

Khosravi, Shahram; Wong, Ronald P.C.; Ardekani, Gholamreza Safaee; Zhang, G; Martinka, Magdalena; Ong, Christopher J.; Li, G

doi:10.1038/bjc.2013.688

Cited by 42 publications

(56 citation statements)

References 34 publications

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“…These effects on survival times suggest that EIF5A2 is not only important in malignant transformation, but also may serve as a driver of tumor progression. Previous studies have demonstrated that EIF5A2 exhibits its tumorigenic effects via activation of the phosphoinositide-3-kinase/Rac-α serine/threonine-protein kinase signaling pathway (15,25) and its induction of matrix metalloproteinase 2 protein expression (26). In addition, EIF5A2 reduces expression of E-cadherin and increases expression of Vimentin (26,27), and may activate transforming protein RhoA precursor/Rac1 signaling pathways (24).…”

Section: Discussionmentioning

confidence: 99%

“…EIF5A2 has been implicated in a number of cancers, including bladder cancer, colorectal cancer, pancreatic adenocarcinoma, esophageal squamous cell carcinoma, gastric adenocarcinoma, breast cancer, prostate adenocarcinoma, hepatocellular carcinoma, ovarian cancer and melanoma (9,(14)(15)(16)(17)(18)(19)(20)(21)(22). Patients with esophageal squamous cell carcinoma, bladder cancer and pancreatic adenocarcinoma in which EIF5A2 is overexpressed have been demonstrated to exhibit statistically significantly shorter survival times (14,17,20).…”

Section: Discussionmentioning

confidence: 99%

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Knockdown of EIF5A2 inhibits the malignant potential of non-small cell lung cancer cells

Chen

Zhang

et al. 2018

Oncol Lett

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Abstract. Eukaryotic translation initiation factor 5A2(EIF5A2) has been demonstrated to be upregulated in numerous types of human cancer and is associated with cancer progression. However, the expression and role of EIF5A2 in non-small cell lung cancer (NSCLC) remains unclear. In the present study, the role of EIF5A2 in NSCLC was investigated, in addition to the underlying molecular mechanisms by which EIF5A2 acts. Relative EIF5A2 expression levels were determined in NSCLC cells and compared with levels in non-cancerous lung tissues. Short interfering (si)RNA targeted against EIF5A2 was used to knock down EIF5A2 levels in NSCLC cells. Cell proliferation, apoptosis rate, migration ability and invasion ability were determined in untreated and siRNA-treated NSCLC cells, in addition to the relative protein expression levels of various tumorigenic proteins and E-cadherin. EIF5A2 expression was significantly higher in NSCLC tissues compared with adjacent normal tissues. Knockdown of EIF5A2 in the NSCLC cells significantly inhibited cell proliferation and induced apoptosis. Furthermore, EIF5A2 silencing suppressed cell migratory and invasive capacities in vitro. Silencing of EIF5A2 in the NSCLC cells resulted in the downregulation of the tumorigenic proteins, apoptosis regulator Bcl-2 and myc proto-oncogene protein, and upregulation of E-cadherin, suggesting that EIF5A2 promotes proliferation and metastasis through these proteins. EIF5A2 may therefore serve as a novel therapeutic target for the treatment of NSCLC.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Knockdown of EIF5A2 inhibits the malignant potential of non-small cell lung cancer cells

Chen

Zhang

et al. 2018

Oncol Lett

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“…Therefore, overexpressing miR-4633-5p suppressed the invasiveness and secretion, but not transcription or translation, of MMP2 in A375 cells in vitro. [12,13]. Therefore, we evaluated the phosphorylation status of Akt, its upstream regulators (PDK1 and PTEN) and its downstream target (GSK-3β) upon overexpression of miR-4633-5p [12,13].…”

Section: Overexpression Of Mir-4633-5p Suppressed Invasiveness and Sementioning

confidence: 99%

“…[12,13]. Therefore, we evaluated the phosphorylation status of Akt, its upstream regulators (PDK1 and PTEN) and its downstream target (GSK-3β) upon overexpression of miR-4633-5p [12,13]. In both A375 cells and M435S cells, cells transfected with mir-4633-expressing plasmid showed decreased expression of pAktS473, pAktT308, pPDK1S241, pPTENS380 and pGSK-3βS9 compared with those transfected with control plasmid (Fig.…”

Section: Overexpression Of Mir-4633-5p Suppressed Invasiveness and Sementioning

confidence: 99%

“…Akt responds to numerous upstream signals by altering its cellular distribution and kinase activity, which subsequently leads to an altered phosphorylation status of its downstream targets. In melanoma, Akt was reported to promote tumor growth, metastasis and development of chemoresistance [13]. Furthermore, the phosphorylation status of Akt was also associated with activity of MMP2 (matrix metalloproteinase-2) in melanoma, which cooperatively expedites the invasion of melanoma cells and, thus, metastasis [14].…”

Section: Introductionmentioning

confidence: 99%

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Identification and Functional Evaluation of miR-4633-5p as a Biomarker and Tumor Suppressor in Metastatic Melanoma

Zou

Zhu

Liu

et al. 2018

Cell Physiol Biochem

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Background/Aims: Sinonasal mucosal melanoma (SMM) is a rare but extremely aggressive disease. Interestingly, however, as lethal as SMM, a few patients could survive for over 5 years without metastasis. However, biomarkers for metastatic SMM are lacking. Methods: Laser-capture microdissection combined with microRNA microarray and RT-qPCR was performed in formalin-fixed paraffin-embedded tissue samples from SMM patients whose follow-up studies were carried out in parallel. In vitro cell proliferation and invasion assays, gelatin zymography, western blot analysis and RT-qPCR were performed in melanoma cell lines. Results: In the discovery stage, miR-4633-5p expressed differentially in sinonasal mucosal melanoma patients with short and long disease-specific survival. Subsequent large-sample validation revealed that expression of miR-4633-5p was lower in metastatic SMM than in non-metastatic patients (P< 0.001). Moreover, miR-4633-5p^low was able to identify metastatic SMM with specificity of 100% (5/5) and sensitivity of 87.5% (21/24). Multivariate analysis further pinpointed miR-4633-5p as an independent marker for metastasis (relative risk: 54.22, P< 0.001). In vitro, overexpression of miR-4633-5p suppressed the growth and invasiveness of melanoma cells through inhibiting activation of Akt pathway and secretion of MMP2, while knockdown of miR-4633-5p reversed the inhibitory effects. Conclusion: Our findings underpin miR-4633-5p as a predictive biomarker in metastatic SMM and a pivotal tumor suppressor that negatively regulates the invasive growth of melanoma cells. Quantitative detection of miR-4633-5p can diagnostically predict the risk of metastasis in SMM patients, which, in turn, may lead to more personalized treatment with better prognosis.

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Dacarbazine alone or associated with melanoma‐bearing cancer pain model induces painful hypersensitivity by TRPA1 activation in mice

Brusco

Puma

Chiepe

et al. 2019

Intl Journal of Cancer

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Antineoplastic therapy has been associated with pain syndrome development characterized by acute and chronic pain. The chemotherapeutic agent dacarbazine, used mainly to treat metastatic melanoma, is reported to cause painful symptoms, compromising patient quality of life. Evidence has proposed that transient receptor potential ankyrin 1 (TRPA1) plays a critical role in chemotherapy‐induced pain syndrome. Here, we investigated whether dacarbazine causes painful hypersensitivity in naive or melanoma‐bearing mice and the involvement of TRPA1 in these models. Mouse dorsal root ganglion (DRG) neurons and human TRPA1‐transfected HEK293 (hTRPA1‐HEK293) cells were used to evaluate the TRPA1‐mediated calcium response evoked by dacarbazine. Mechanical and cold allodynia were evaluated after acute or repeated dacarbazine administration in naive mice or after inoculation of B16‐F10 melanoma cells in C57BL/6 mice. TRPA1 involvement was investigated by using pharmacological and genetic tools (selective antagonist or antisense oligonucleotide treatment and Trpa1 knockout mice). Dacarbazine directly activated TRPA1 in hTRPA1‐HEK293 cells and mouse DRG neurons and appears to sensitize TRPA1 indirectly by generating oxidative stress products. Moreover, dacarbazine caused mechanical and cold allodynia in naive but not Trpa1 knockout mice. Also, dacarbazine‐induced nociception was reduced by the pharmacological TRPA1 blockade (antagonism), antioxidants, and by ablation of TRPA1 expression. TRPA1 pharmacological blockade also reduced dacarbazine‐induced nociception in a tumor‐associated pain model. Thus, dacarbazine causes nociception by TRPA1 activation, indicating that this receptor may represent a pharmacological target for treating chemotherapy‐induced pain syndrome in cancer patients submitted to antineoplastic treatment with dacarbazine.

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Role of EIF5A2, a downstream target of Akt, in promoting melanoma cell invasion

Cited by 42 publications

References 34 publications

Knockdown of EIF5A2 inhibits the malignant potential of non-small cell lung cancer cells

Knockdown of EIF5A2 inhibits the malignant potential of non-small cell lung cancer cells

Identification and Functional Evaluation of miR-4633-5p as a Biomarker and Tumor Suppressor in Metastatic Melanoma

Dacarbazine alone or associated with melanoma‐bearing cancer pain model induces painful hypersensitivity by TRPA1 activation in mice

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