Beclin1 overexpression suppresses tumor cell proliferation and survival via an autophagy‑dependent pathway in human synovial sarcoma cells

Zhu, Jia‐Lin; Cai, Yongsong; Xu, Ke; Ren, Xiaoyu; Sun, Jian; Lu, Shemin; Chen, Jinghong; Xu, Peng

doi:10.3892/or.2018.6599

Cited by 25 publications

(21 citation statements)

References 54 publications

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“…One outcome of this unexpected neratinib biology was that the drug regulated the Hippo Pathway. Coordinated signaling by RAS proteins and the co-transcriptional regulators YAP and TAZ has been shown to promote tumor growth, invasion and chemotherapy resistance (23–26). Individually, neratinib as well as [pazopanib + entinostat] exposure increased the phosphorylation of YAP and TAZ and interacted together to further enhance phosphorylation of the co-transcription factors.…”

Section: Discussionmentioning

confidence: 99%

“…In our sarcoma studies we also discovered that Rubicon knock down was significantly more protective against neratinib, [pazopanib + entinostat] and [pazopanib + entinostat + neratinib] when compared to Beclin1/ATG5. Although there are no published studies discussing LAP in sarcomas, significant literature exists defining the role of autophagy in the biology of sarcomas (23–26). For example, over-expression of Beclin1 can promote autophagy-dependent sarcoma growth and resistance to chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

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The Lethality of [Pazopanib + HDAC Inhibitors] Is Enhanced by Neratinib

et al. 2019

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Sarcomas are a diverse set of malignancies. For soft tissue sarcomas, the kinase and chaperone inhibitor pazopanib is a standard of care therapeutic. Previously, we demonstrated that HDAC inhibitors enhanced pazopanib lethality against sarcoma and other tumor cell types in vitro and in vivo . The present studies defined mechanisms of drug-combination resistance. Exposure of sarcoma and PDX ovarian carcinoma cells to [pazopanib + entinostat] caused a prolonged activation of ERBB1 and transient/prolonged activations of ERBB2, c-KIT, and c-MET, in a cell-specific fashion. The activities of mTORC1, mTORC2, GRP78, HSP90, and HSP70 were reduced, expression of Beclin1 and ATG5 enhanced, and the ATM-AMPK-ULK1-ATG13-Beclin1/ATG5 pathway activated. Inhibition of ERBB1/2/4 using neratinib or of c-MET using crizotinib significantly enhanced [pazopanib + entinostat] lethality. For neratinib with [pazopanib + entinostat], this effect correlated with reduced phosphorylation and expression of ERBB1, ERBB2, c-KIT, and c-MET and reduced expression, regardless of mutational status, of N-RAS and K-RAS. [Pazopanib + entinostat + neratinib] reduced the phosphorylation of the Hippo pathway proteins MST1/3/4 and MOB1 whereas this treatment increased the phosphorylation of LATS1, YAP, and TAZ. The activation of ATM, ULK-1, and eIF2α was further enhanced by [pazopanib + entinostat + neratinib] as was the expression of ATG5 and Beclin1. Compared to other manipulations, knock down of eIF2α or over-expression of BCL-XL significantly reduced killing by the three-drug interaction. In vivo , pazopanib and entinostat, and also neratinib and entinostat, both combined to significantly suppress the growth of sarcoma tumors.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The Lethality of [Pazopanib + HDAC Inhibitors] Is Enhanced by Neratinib

et al. 2019

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“…Hence, in the present study, the autophagic response of OS cells was investigated by western blot analysis and mRFP-GFP-LC3 adenovirus assay. Beclin1, a protein whose levels are positively associated with the level of autophagy, was overexpressed in the two cell lines in a dose-dependent manner following treatment with PI-1840, and knowledge of its anticancer activity has been emerging in recent years (41). To inhibit autophagy of the OS cells, chloroquine was used, and subsequently a CCK-8 assay was performed to determine whether the PI-1840-induced autophagy could influence the survival rate.…”

Section: Discussionmentioning

confidence: 99%

Non‑covalent proteasome inhibitor PI‑1840 induces apoptosis and autophagy in osteosarcoma cells

Chen

Xie

et al. 2019

Oncol Rep

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Osteosarcoma (OS) is the predominant form of primary bone malignancy in children and adolescents. Although the combination of chemotherapy and modified surgical therapy leads to marked improvements in the survival rate, the therapeutic outcomes remain unsatisfactory. Therefore, the identification of novel drugs with higher efficacy and fewer side-effects is urgently required. Proteasome inhibitors have been approved by the Food and Drug Administration (FDA) for the treatment of certain cancers, although none of them are directed against OS. Non-covalent proteasome inhibitors, such as PI-1840, are superior to covalent ones in numerous respects in view of their chemical structure; however, to date, no studies have been published on the effects of non-covalent proteasome inhibitors on OS cells. In the present study, the antineoplastic effects of PI-1840 were systematically evaluated in the OS cell lines, MG-63 and U2-OS. Cell viability and morphological changes were assessed by Cell Counting Kit-8 (CCK-8) and live/dead assays. The cell cycle was analyzed using flow cytometry (FCM) and western blot analysis (assessing the levels of the proteins p21, p27, and the tyrosine kinase, WEE1). The extent of cell apoptosis and autophagy were assessed by FCM, western blot analysis [of the apoptosis-associated proteins, microtubule-associated protein 1 light chain 3 α (LC3) and Beclin1], and mRFP-GFP-LC3 adenovirus transfection assay. Transwell and wound healing assays, and western blot analysis of the matrix metalloproteinases (MMPs)2 and 9 were performed to preliminarily evaluate the migration and invasion capability of the cells. In the present study, our results revealed that PI-1840 inhibited the proliferation of OS cells and induced apoptosis, partly due to attenuation of the nuclear factor-κB (NF-κB) pathway. In addition, PI-1840-induced autophagy was detected, and inhibiting the autophagy of the OS cells led to an increase in the survival rate of the U2-OS cells rather than of the MG-63 cells. Furthermore, PI-1840 attenuated the migration and invasion capabilities of the OS cells. In conclusion, the present study revealed PI-1840 to be a promising drug for the treatment of OS.

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“…FLIP has been shown to inhibit LC3 lipidation by competitive interaction with ATG3, which in turn blocks autophagy [16]. Moreover, Zhu J., et al have shown that the inhibition of survivin through the use of siRNA enhanced autophagy by upregulating Beclin-1 [29]. Therefore, in order to explain the mechanism by which PRFR sensitizes TNF-α-induced autophagy, the modulatory effect of PRFR on TNF-α induced FLIP, Bcl-xl, and survivin expression levels was examined.…”

Section: Discussionmentioning

confidence: 99%

Proanthocyanidin-Rich Fractions from Red Rice Extract Enhance TNF-α-Induced Cell Death and Suppress Invasion of Human Lung Adenocarcinoma Cell A549

2019

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Tumor necrosis factor-alpha (TNF-α) plays a key role in promoting tumor progression, such as stimulation of cell proliferation and metastasis via activation of NF-κB and AP-1. The proanthocyanidin-rich fraction obtained from red rice (PRFR) has been reported for its anti-tumor effects in cancer cells. This study investigated the molecular mechanisms associated with PRFR on cell survival and metastasis of TNF-α-induced A549 human lung adenocarcinoma. Notably, PRFR enhanced TNF-α-induced A549 cell death when compared with PRFP alone and caused a G0-G1 cell cycle arrest. Although, PRFR alone enhanced cell apoptosis, the combination treatment induced the cells that had been enhanced with PRFR and TNF-α to apoptosis that was less than PRFR alone and displayed a partial effect on caspase-8 activation and PARP cleavage. By using the autophagy inhibitor; 3-MA attenuated the effect of how PRFR enhanced TNF-α-induced cell death. This indicates that PRFR not only enhanced TNF-α-induced A549 cell death by apoptotic pathway, but also by induction autophagy. Moreover, PRFR also inhibited TNF-α-induced A549 cell invasion. This effect was associated with PRFR suppressed the TNF-α-induced level of expression for survival, proliferation, and invasive proteins. This was due to reduce of MAPKs, Akt, NF-κB, and AP-1 activation. Taken together, our results suggest that TNF-α-induced A549 cell survival and invasion are attenuated by PRFR through the suppression of the MAPKs, Akt, AP-1, and NF-κB signaling pathways.

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Beclin1 overexpression suppresses tumor cell proliferation and survival via an autophagy‑dependent pathway in human synovial sarcoma cells

Cited by 25 publications

References 54 publications

The Lethality of [Pazopanib + HDAC Inhibitors] Is Enhanced by Neratinib

The Lethality of [Pazopanib + HDAC Inhibitors] Is Enhanced by Neratinib

Non‑covalent proteasome inhibitor PI‑1840 induces apoptosis and autophagy in osteosarcoma cells

Proanthocyanidin-Rich Fractions from Red Rice Extract Enhance TNF-α-Induced Cell Death and Suppress Invasion of Human Lung Adenocarcinoma Cell A549

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