ARK5 promotes doxorubicin resistance in hepatocellular carcinoma via epithelial–mesenchymal transition

Tao, Xiuxiang; Zhang, Jian; Chen, Wei; Pan, Sheng-Jing; Zhi, Xu; Wen, Liang; Zhou, Yue; Chen, Bryan Wei; Qiu, Junyu; Zhang, Yun; Yang, Qi; Feng, Xin‐Hua; Bai, Xueli; Liang, Tingbo

doi:10.1016/j.canlet.2016.04.026

Cited by 42 publications

(40 citation statements)

References 30 publications

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“…notably, chemoresistance to dox represents a major challenge for the treatment of Hcc. a previous study demonstrated that AMP-activated protein kinase family member 5 (ARK5) is able to modulate the resistance of HCC to Dox via epithelial-mesenchymal transition (eMT) (9). a previous study identified that semaphorins regulate cell migration, enhancing the resistance of Hcc to dox (10).…”

Section: Low-intensity Ultrasound Enhances the Antitumor Effects Of Dmentioning

confidence: 99%

Low‑intensity ultrasound enhances the antitumor effects of doxorubicin on hepatocellular carcinoma cells through the ROS‑miR‑21‑PTEN axis

Xia¹,

Zeng²,

Zheng

2020

Mol Med Report

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Hepatocellular carcinoma (Hcc) is a type of liver cancer and is a leading cause of cancer-associated mortality. in china, ~466,000 patients are diagnosed with Hcc and it is responsible for ~422,000 cases of mortality each year. Surgery is the most effective treatment available; however it is only suitable for patients with early-stage Hcc. chemotherapy has been confirmed as a necessary treatment for patients with advanced Hcc, although drug resistance may limit its clinical outcome. low intensity ultrasound (liuS) represents a novel therapeutic approach to treat patients with Hcc; however, its underlying molecular mechanism remains unclear. in the present study, cell viability, apoptosis and reactive oxygen species (roS) generation were determined via cell counting Kit-8, flow cytometry and 2',7'-dichlorofluorescein diacetate assays, respectively. The expression of mirna in Hcc cells following exposure to liuS and doxorubicin (dox) was analyzed using a microarray and reverse transcription-quantitative polymerase chain reaction analysis. it was revealed treatment with liuS in combination with dox was able to induce apoptosis of Huh7 cells, increasing the intracellular levels of reactive oxygen species (roS) and malondialdehyde. Glutathione peroxidase and superoxide dismutase 1 are roS-scavenging enzymes, which serve important roles in the oxidative balance, preventing oxidative stress. The protein expression levels of these two enzymes were significantly decreased following treatment with liuS combined with dox. The present results suggested that liuS may decrease dox resistance in Hcc cells and that liuS may be combined with chemotherapy to treat Hcc. By performing microarray analysis, the expression levels of microrna-21 (mir-21) were decreased following treatment with liuS combined with dox. Functional experiments showed that knockdown of mir-21 enhanced the antitumor activity of dox, whereas overexpression of mir-21 reversed these effects. Phosphatase and tensin homolog (PTen), a well-known tumor suppressor, was revealed to be a direct target of mir-21, and its translation was suppressed by mir-21. Finally, it was determined that combined treatment of liuS and dox induced anticancer effects by blocking the activation of the aKT/mTor pathway, as demonstrated by the downregulation of phosphorylated (p-)aKT and p-mTor; n-acetylcysteine, a general roS inhibitor reversed the suppressive effects on the aKT/mTor pathway mediated by liuS and dox. collectively, the present results suggested that liuS increased cell sensitivity to dox via the roS/mir-21/PTen pathway. chemotherapy combined with liuS may represent a novel effective therapeutic strategy to treat patients with advanced Hcc.

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Section: Low-intensity Ultrasound Enhances the Antitumor Effects Of Dmentioning

confidence: 99%

Low‑intensity ultrasound enhances the antitumor effects of doxorubicin on hepatocellular carcinoma cells through the ROS‑miR‑21‑PTEN axis

Xia¹,

Zeng²,

Zheng

2020

Mol Med Report

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“…32 HCC ARK5 stimulated EMT, and ARK5 suppression restored E-cadherin and vimentin expression. 46 HCC Knockdown of ARK5 reverse the process of EMT. 47 HNSCC ARK5 is involved in the invasion and EMT induction of HNSCC.…”

Section: Nsclcmentioning

confidence: 99%

“…Regulates m-TOR phosphorylation induced by IGF-1 43 NSCLC Phosphorylation of m-TOR and induced the phosphorylation of two mTOR downstream (p70S6K1 and 4Ebinding protein 1 (4E-BP1)) 44 PI3K-Akt Breast PI3K/Akt/ARK5 pathways activity increased the invasiveness of MDA-MB-231 53 Colorectal Invasion activity was further increased by Akt expression and decreased by PI-3K inhibitor LY294002 treatment 46,47 . Knockdown of ARK5 expression was associated with reduced invasion and metastasis of GC cell, further confirming the role of EMT in tumor invasion and metastasis 32 .…”

Section: Gliomamentioning

confidence: 99%

Deciphering the role of AMPK-related kinase 5 in human cancer progression and metastasis

2019

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Malignancies related mortality is currently growing at an alarming rate. Early detection of cancer is vital in order to improve survival rates of cancer patients, and biomarker detection is regarded as one of the most promising approaches. Recent studies have reported that elevated ARK5 expression is associated with tumor progression and metastasis in several human malignancies. Several pathways are also influenced by the presence of ARK5, most notably the PI3k-Akt pathway, m-TOR phosphorylation, and several pathways that induce increased tumor invasion activity. Additionally, ARK5 expression are linked to miR-1181 down-regulation, which promotes epithelial mesenchymal transformation in ovarian cancer cells. Furthermore, ARK5 gene transcription is also affected by the interaction of c-MAF and MAFB with both MARE core sequences present in the ARK5 promoter. Based on the current evidences, ARK5 might be the master regulator of cancer progression and metastasis, which could potentially serve as a novel target for cancer therapies.

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“…However, traditional cytotoxic chemotherapeutic drugs, such as doxorubicin and paclitaxel, exhibit limited clinical efficacy, due to systemic toxicity, lack of selectivity, and drug resistance. 2,3 The effectiveness of combination therapy is supported by clinical research, which shows superior antitumor efficacy than single-drug therapy via different antitumor approaches. [4][5][6] Antiangiogenesis, a promising antitumor strategy blocking the development of tumor blood vessels, is widely accepted.…”

Section: Introductionmentioning

confidence: 99%

<p>Liver-targeted liposomes for codelivery of curcumin and combretastatin A4 phosphate: preparation, characterization, and antitumor effects</p>

Jiang¹,

Li²,

Tian³

et al. 2019

IJN

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Background: Recent efforts have been focused on combining two or more therapeutic approaches with different mechanisms to enhance antitumor therapy. Moreover, nanosize drugdelivery systems for codelivering two drugs with proapoptotic and antiangiogenic activities have exhibited great potential in efficient treatment of cancers. Methods: Glycyrrhetinic acid (GA)-modified liposomes (GA LPs) for liver-targeted codelivery of curcumin (Cur) and combretastatin A4 phosphate (CA4P) were prepared and characterized. In vitro cellular uptake, cytotoxicity, cell migration, in vivo biodistribution, antitumor activity, and histopathological studies were performed. Results: Compared with unmodified LPs (Cur-CA4P LPs), Cur-CA4P/GA LPs were taken up effectively by human hepatocellular carcinoma cells (BEL-7402) and showed higher cytotoxicity than free drugs. In vivo real-time near-infrared fluorescence-imaging results indicated that GA-targeted LPs increased accumulation in the tumor region. Moreover, Cur-CA4P/GA LPs showed stronger inhibition of tumor proliferation than Cur, Cur + CA4P, and Cur-CA4P LPs in vivo antitumor studies, which was also verified by H&E staining. Conclusion: GA-modified LPs can serve as a promising nanocarrier for liver-targeted co-delivery of antitumor drugs against hepatocellular carcinoma.

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ARK5 promotes doxorubicin resistance in hepatocellular carcinoma via epithelial–mesenchymal transition

Cited by 42 publications

References 30 publications

Low‑intensity ultrasound enhances the antitumor effects of doxorubicin on hepatocellular carcinoma cells through the ROS‑miR‑21‑PTEN axis

Low‑intensity ultrasound enhances the antitumor effects of doxorubicin on hepatocellular carcinoma cells through the ROS‑miR‑21‑PTEN axis

Deciphering the role of AMPK-related kinase 5 in human cancer progression and metastasis

<p>Liver-targeted liposomes for codelivery of curcumin and combretastatin A4 phosphate: preparation, characterization, and antitumor effects</p>

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