VEGF‐C mediates RhoGDI2‐induced gastric cancer cell metastasis and cisplatin resistance

Cho, Hee Jun; Kim, In Kyu; Park, Sun-Mi; Baek, Kyoung Eun; Nam, In-Koo; Park, Seung-Ho; Ryu, Ki-Jun; Choi, Jungil; Ryu, Jinhyun; Hong, Soon Chan; Jeong, Sang‐Ho; Lee, Young-Joon; Ko, Gyung‐Hyuck; Kim, Jae Won; Lee, Chang Won; Kang, Sang Soo; Yoo, Ji Myong

doi:10.1002/ijc.28801

Cited by 42 publications

(35 citation statements)

References 45 publications

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“…Consistently, the downstream molecules of AKT, such as c-Myc, and AKT-related anti-apoptotic, metastatic or angiogenic molecules could be efficiently suppressed by KU0060648 treatment. Many studies have shown that these substrates participate in the resistance of certain cancers to chemotherapy [51 - 55]. Taken together, these data revealed that the single agent of KU0060648 or in combination with TMZ in glioma treatment mainly depended on inhibition of AKT signaling.…”

Section: Discussionmentioning

confidence: 82%

Targeting hyperactivated DNA-PKcs by KU0060648 inhibits glioma progression and enhances temozolomide therapy via suppression of AKT signaling

Lan

Zhao

et al. 2016

Oncotarget

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The overall survival remains undesirable in clinical glioma treatment. Inhibition of DNA-PKcs activity by its inhibitors suppresses tumor growth and enhances chemosensitivity of several tumors to chemotherapy. However, whether DNA-PKcs could be a potential target in glioma therapy remains unknown. In this study, we reported that the hyperactivated DNA-PKcs was profoundly correlated with glioma malignancy and observe a significant association between DNA-PKcs activation and survival of the glioma patients. Our data also found that inhibition of DNA-PKcs by its inhibitor KU0060648 sensitized glioma cells to TMZ in vitro. Specifically, we demonstrated that KU0060648 interrupted the formation of DNA-PKcs/AKT complex, leading to suppression of AKT signaling and resultantly enhanced TMZ efficacy. Combination of KU0060648 and TMZ substantially inhibited downstream effectors of AKT. The in vivo results were similar to those obtained in vitro. In conclusion, this study indicated that inhibition of DNA-PKcs activity could suppress glioma malignancies and increase TMZ efficacy, which was mainly through regulation of the of AKT signaling. Therefore, DNA-PKcs/AKT axis may be a promising target for improving current glioma therapy.

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Section: Discussionmentioning

confidence: 82%

Targeting hyperactivated DNA-PKcs by KU0060648 inhibits glioma progression and enhances temozolomide therapy via suppression of AKT signaling

Lan

Zhao

et al. 2016

Oncotarget

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“…This evidence suggests that the P5 and P6 peptides not only suppressed VEGFR-3 activation but also subsequently diminished cancer cell migration and invasion. It has been reported that VEGF-C helps cancer cells to survive Taxol treatment via downregulation of mTORC1 function in prostate and pancreatic cancers [ 17 ]; additionally, VEGF-C was shown to enhance cisplatin-resistance through NF-κB activation in gastric cancer [ 18 ]. Moreover, VEGF-C-induced Akt activation has been suggested to promote prostate cancer cell survival [ 19 ].…”

Section: Resultsmentioning

confidence: 99%

Novel peptides suppress VEGFR-3 activity and antagonize VEGFR-3-mediated oncogenic effects

Chang

et al. 2014

Oncotarget

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Vascular endothelial growth factor receptor 3 (VEGFR-3) supports tumor lymphangiogenesis. It was originally identified as a lymphangiogenic factor expressed in lymphatic endothelial cells. VEGFR-3 was detected in advanced human malignancies and correlated with poor prognosis. Our previous studies show that activation of the VEGF-C/VEGFR-3 axis promotes cancer metastasis and is associated with clinical progression in patients with lung cancer, indicating that VEGFR-3 is a potential target for cancer therapy. In this study, we developed eight peptides targeting VEGFR-3. Two peptides strongly inhibited the kinase activity of VEGFR-3 and suppressed VEGF-C-mediated invasion of cancer cells. Moreover, these peptides abolished VEGF-C-induced drug resistance and tumor initiating cell formation. This study demonstrates the therapeutic potential of VEGFR-3-targeting peptides.

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“…A Korea group showed RhoGDI2 confer gastric cancer cells resistance to cisplatin induced apoptosis by several mechanisms. VEGF-C [ 7 ], 14-3-3σ [ 8 ], PLCγ [ 5 ], Bcl-2 [ 6 ] may mediate the effects of RhoGDI2 in drug resistance. However, our previous study showed a different mechanism [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

RhoGDI2 up-regulates P-glycoprotein expression via Rac1 in gastric cancer cells

Zheng

Liu

2015

Cancer Cell Int

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Multidrug resistance (MDR) is a major clinical obstacle in treatment of gastric cancer. Previously, using 2D electrophoresis-mass spectrometry, we identified RhoGDI2 as a contributor to 5-FU resistance in colon cancer cells, and also confer gastric cancer cells resistance to 5-FU. Here, we reported RhoGDI2 also induced MDR in gastric cancer cell line (MKN-45). To explore the underlining mechanism, we detected the mRNA, protein expression, activity of P-glycoprotein (P-gp) in MKN-45 stably transfected with RhoGDI2 expressing or control vector. All the mRNA, protein level, activity were increased by 130%, 230%, 35% respectively after ectopic expression of RhoGDI2. RhoGDI2 was correlated with P-gp expression in gastric cancer tissues as detected by immunohistochemistry. To further study how RhoGDI2 up-regulates P-gp expression, we tested the activity of Rac1 in MKN-45/RhoGDI2 and MKN-45/GFP. Ectopic expression of RhoGDI2 increased Rac1 activity (P < 0.05). For more important, silencing of Rac1 expression by siRNA decreased P-gp expression to undetectable level. Overall, these findings suggest that RhoGDI2 up-regulates P-gp expression via Rac1 to induce MDR.Electronic supplementary materialThe online version of this article (doi:10.1186/s12935-015-0190-4) contains supplementary material, which is available to authorized users.

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VEGF‐C mediates RhoGDI2‐induced gastric cancer cell metastasis and cisplatin resistance

Cited by 42 publications

References 45 publications

Targeting hyperactivated DNA-PKcs by KU0060648 inhibits glioma progression and enhances temozolomide therapy via suppression of AKT signaling

Targeting hyperactivated DNA-PKcs by KU0060648 inhibits glioma progression and enhances temozolomide therapy via suppression of AKT signaling

Novel peptides suppress VEGFR-3 activity and antagonize VEGFR-3-mediated oncogenic effects

RhoGDI2 up-regulates P-glycoprotein expression via Rac1 in gastric cancer cells

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