GABAA receptor-binding protein promotes sensitivity to apoptosis induced by chemotherapeutic agents

Rho, Seung Bae; Byun, Hyun-Jung; Kim, Boh-Ram; Kim, Ik Sun; Lee, Jeong Heon; Yoo, Richard; Park, Sung Taek; Park, Sung Ho

doi:10.3892/ijo.2013.1866

Cited by 9 publications

(7 citation statements)

References 59 publications

(51 reference statements)

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“…For example, Wu et al showed that GABARAP promotes bone marrow mesenchymal stem cell-based osteoarthritis cartilage regeneration through the inhibition of the PI3K/AKT/mTOR signaling pathway [16]. Rho et al reported that GABARBP inactivates cisplatin-induced dephosphorylation of the PI3K/Akt signaling pathway and promotes the sensitivity of ovarian cancer to apoptosis [30]. In line with these studies, we found that downregulation of GABARAP expression increased p-AKT and p-mTOR levels and induced EMT.…”

Section: Discussionsupporting

confidence: 88%

GABARAP Suppresses EMT and Breast Cancer Progression Via the AKT/mTOR Signaling Pathway

Liu

Wang

Lei

et al. 2020

Preprint

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Background: Recent studies document that γ-aminobutyric acid type A (GABAA) receptor-associated protein (GABARAP) plays an important role in cancer autophagy. However, little is known about its role in tumor invasion, migration and metastasis. Here, the authors investigated the expression and significance of GABARAP in breast cancer. Method: A large group of clinical samples was assessed to detect GABARAP expression and its associations with clinicopathological features and prognosis. Gain- and loss-of-function experiments in cell lines and mouse xenograft models were performed to elucidate the function and underlying mechanisms of GABARAP-regulated tumor progression. Results: We analyzed GABARAP levels in clinical breast cancer samples and cell lines and confirmed that GABARAP was negatively correlated with advanced clinicopathologic features, such as tumor size (P=0.025) and TNM stage (P=0.001). Importantly, patients with low GABARAP levels had a poor prognosis (p = 0.0047). Functionally, our data revealed that GABARAP can inhibit proliferation, migration and invasion in vitro and in vivo. Importantly, low levels of GABARAP induced epithelial-mesenchymal transition (EMT), one of the most important mechanisms for the promotion of tumor metastasis, in breast cancer cells. Mechanistically, low levels of GABARAP increased the levels of p-AKT (S473) and p-mTOR (S2448), and a specific AKT pathway inhibitor reversed the downregulation of GABARAP-induced tumor progression. In clinical breast cancer specimens, immunohistochemistry (IHC) revealed that the distribution and intensity of GABARAP expression were negatively correlated with those of matrix metalloproteinase (MMP) 2 (P=0.0013) and MMP14 (P=0.019). Conclusions: Collectively, these data indicated that GABARAP suppressed the malignant behaviors of breast cancer cells, illuminating that the possible mechanism acts via the AkT/mTOR pathway. Targeting GABARAP may provide a potential diagnosis and treatment strategy for breast cancer.

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Section: Discussionsupporting

confidence: 88%

GABARAP Suppresses EMT and Breast Cancer Progression Via the AKT/mTOR Signaling Pathway

Liu

Wang

Lei

et al. 2020

Preprint

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“…Recent studies have reported that GABARAP plays a crucial role in modulating the level of autophagy. [14]. In line with these studies, we found that downregulation of GABARAP expression increased p-AKT and p-mTOR levels and induced EMT.…”

Section: Discussionsupporting

confidence: 85%

“…It is a key player in the intracellular trafficking of these receptors [7,8]. GABARBP binds to various intracellular proteins, which are all associated with vesicle transport processes, autophagy, apoptosis, which include the cytoskeleton, tubulin, gephyrin, the clathrin heavy chain, p130/phospholipase C-related inactive protein (PRIP), transferrin receptor, Unc-51-like kinase, Ras-related protein 24, angiotensin II type 1 (AT1) receptor [9][10][11][12][13][14]. Recently, GABARAP has been reported to play a key role in inhibiting inflammation progression [15] and regulating angiogenic activity [16].…”

mentioning

confidence: 99%

GABARAP suppresses EMT and breast cancer progression via the AKT/mTOR signaling pathway

Liu

Wang

Lei

et al. 2020

Preprint

View full text Add to dashboard Cite

Background γ-aminobutyric acid type A (GABAA) receptor-associated protein (GABARAP) is rarely studied in tumor progression. Here, the authors investigated the expression and significance of GABARAP in breast cancer. Method: A large group of clinical samples was assessed to detect GABARAP expression and its associations with clinicopathological features and prognosis. Gain- and loss-of-function experiments in cell lines and mouse xenograft models were performed to elucidate the function and underlying mechanisms of GABARAP-regulated tumor progression. Results We analyzed GABARAP levels in clinical breast cancer samples and cell lines and confirmed that GABARAP was negatively correlated with advanced clinicopathologic features, such as tumor size (P = 0.025) and TNM stage (P = 0.001). Importantly, patients with low GABARAP levels had a poor prognosis (p = 0.0047). Functionally, our data revealed that GABARAP can inhibit proliferation, migration and invasion in vitro and in vivo. Importantly, low levels of GABARAP induced epithelial-mesenchymal transition (EMT), one of the most important mechanisms for the promotion of tumor metastasis, in breast cancer cells. Mechanistically, low levels of GABARAP increased the levels of p-AKT (S473) and p-mTOR (S2448), and a specific AKT pathway inhibitor reversed the downregulation of GABARAP-induced tumor progression. In clinical breast cancer specimens, immunohistochemistry (IHC) revealed that the distribution and intensity of GABARAP expression were negatively correlated with those of matrix metalloproteinase (MMP) 2 (P = 0.0013) and MMP14 (P = 0.019). Conclusions Collectively, these data indicated that GABARAP suppressed the malignant behaviors of breast cancer cells, illuminating that the possible mechanism acts via the AkT/mTOR pathway. Targeting GABARAP may provide a potential diagnosis and treatment strategy for breast cancer.

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“…P27 is a cyclin dependent kinase (CDK) inhibitor which negatively regulates CDK activity at the G0/G1 phase transition. The induction of p27 causes G0/G1 cell cycle arrest [21,22]. The loss of expression or function of p27 has been implicated in the genesis or progression of many human malignancies [23].…”

Section: Resultsmentioning

confidence: 99%

Theaflavin-3,3′-Digallate Suppresses Human Ovarian Carcinoma OVCAR-3 Cells by Regulating the Checkpoint Kinase 2 and p27 kip1 Pathways

Gao

Yin

et al. 2019

Molecules

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Theaflavin-3,3′-digallate (TF3) is a unique polyphenol in black tea. Epidemiological studies have proved that black tea consumption decreases the incidence rate of ovarian cancer. Our former research demonstrated that TF3 inhibited human ovarian cancer cells. Nevertheless, the roles of checkpoint kinase 2 (Chk2) and p27 kip1 (p27) in TF3-mediated inhibition of human ovarian cancer cells have not yet been investigated. In the current study, TF3 enhanced the phosphorylation of Chk2 to modulate the ratio of pro/anti-apoptotic Bcl-2 family proteins to initiate intrinsic apoptosis in a p53-independent manner and increased the expression of death receptors to activate extrinsic apoptosis in OVCAR-3 human ovarian carcinoma cells. In addition, TF3 up-regulated the expression of p27 to induce G0/G1 cell cycle arrest in OVCAR-3 cells. Our study indicated that Chk2 and p27 were vital anticancer targets of TF3 and provided more evidence that TF3 might be a potent agent to be applied as adjuvant treatment for ovarian cancer.

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GABAA receptor-binding protein promotes sensitivity to apoptosis induced by chemotherapeutic agents

Cited by 9 publications

References 59 publications

GABARAP Suppresses EMT and Breast Cancer Progression Via the AKT/mTOR Signaling Pathway

GABARAP Suppresses EMT and Breast Cancer Progression Via the AKT/mTOR Signaling Pathway

GABARAP suppresses EMT and breast cancer progression via the AKT/mTOR signaling pathway

Theaflavin-3,3′-Digallate Suppresses Human Ovarian Carcinoma OVCAR-3 Cells by Regulating the Checkpoint Kinase 2 and p27 kip1 Pathways

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