A novel derivative of valepotriate inhibits the PI3K/AKT pathway and causes Noxa-dependent apoptosis in human pancreatic cancer cells

Yan, Youyou; Shi, Keying; Teng, Fei; Chen, Jing; Che, Jinxin; Dong, Xiaowu; Lin, Nengming; Zhang, Bo

doi:10.1038/s41401-019-0354-1

Cited by 10 publications

(7 citation statements)

References 31 publications

(27 reference statements)

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“…Although ERK1/2 is known to activate the NOXA protein, while in this current study, the ERK1/2 phosphorylation level was not completely inhibited, which could be responsible for NOXA expression. Moreover, the inhibition of Akt protein can also promote NOXA, as shown in other studies 47,48 .…”

Section: Discussionsupporting

confidence: 62%

Chrysin Promotes Temozolomide-induced Apoptosis by Activating p38 MAPK and Suppressing Akt and ERK1/2 in Human Glioblastoma.

Kamarudin¹,

Parhar²

2021

Preprint

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Temozolomide (Tmz) faces the challenges of high chemoresistance and high dose leading to various side-effects. Chrysin exhibits anticancer and adjuvant effects in various cancer models. Nevertheless, chrysin’s synergistic effect with Tmz against Tmz-sensitive and Tmz-resistant human glioblastoma has never been reported. Chrysin and Tmz reduced the viability of A172 and LN18 in concentration- and time-dependent manner, with chrysin exhibited IC50 values lower than Tmz. The combination of chrysin and Tmz enhanced cell death (CI indexes between 0.59–0.98), suggesting synergistic efficacy of chrysin at lower concentrations. Chrysin promoted Tmz-induced phosphatidylserine externalization and depolarization of mitochondrial membrane potential. Chrysin promoted Tmz-induced suppression of pAkt (Ser473) and pERK1/2 (Thr202/Tyr204) while enhanced the phosphorylation of p38 MAPK (Thr180/Tyr182). This further reduced the antiapoptotic proteins (Bcl-2, Bcl-xL, Mcl-1), elevated proapoptotic proteins (Bax, Bad, Bak, PUMA, Noxa), and activated caspase-9 and caspase-3 compared to Tmz treatment alone. Pretreatment with Z-LEHD-FMK and Z-VAD-FMK attenuated apoptosis and restored caspase-9 and − 3 levels. However, pretreatment with Z-IETD-FMK did not suppress the promotion of apoptosis. Collectively, chrysin promotes Tmz-induced apoptosis through p38 MAPK activation and suppression of Akt and ERK1/2. These results suggest chrysin as a potential therapeutic adjuvant to improve Tmz effects in Tmz-sensitive and -resistant GBM.

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Section: Discussionsupporting

confidence: 62%

Chrysin Promotes Temozolomide-induced Apoptosis by Activating p38 MAPK and Suppressing Akt and ERK1/2 in Human Glioblastoma.

Kamarudin¹,

Parhar²

2021

Preprint

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“…[28] Additionally, Amcp, one novel derivative of valepotriate signi cantly inhibited the PI3K/AKT signaling, suppressing the cell viability and Mcl-1 expression in pancreatic cancer cells. [29] In this study, we con rmed 6-P negatively regulated activity of PI3K/AKT signaling via decreasing EGFR.…”

Section: Discussionsupporting

confidence: 52%

[6]-Paradol Suppresses Proliferation and Metastases of Pancreatic Cancer by Decreasing EGFR and Inactivating PI3K/AKT Signaling

Jiang

Wang

Chen

et al. 2021

Preprint

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Background: The underlying mechanism behind the tumorigenesis and progression of pancreatic cancer is not clear, and treatment failure is generally caused by early metastasis, recurrence, drug resistance and vascular invasion. Exploring novel therapeutic regimens is necessary to overcome drug resistance and improve patients outcomes.Methods: Functional assays were performed to investigated the role of 6-Paradol in proliferation and metastasis in vitro and vivo. The interaction between EGFR and 6-P was tested by KEGG enrichment analysis and molecular docking analysis. qRT-PCR was performed to detected the mRNA expression of EGFR in 6-P treated groups. Involvement of the PI3K/AKT pathway was measured by western blotting.Results: 6-P significantly suppressed pancreatic cancer cell proliferation and metastasis. KEGG enrichment analysis and molecular docking analysis suggested that there was an interaction between EGFR and 6-P. In addition, 6-P obviously decreased EGFR protein expression levels but did not change the mRNA of EGFR. 6-P could induce degradation of EGFR through decreasing the protein stability of EGFR and enhancing the ubiquitin-mediated proteasome-dependent degradation,6-P-mediated EGFR degradation led to inactivating PI3K/AKT signaling pathway. However, Ectopic expression of EGFR protein resulted in resistance to 6-P-mediated inactivity of PI3K/AKT signaling and inhibition of malignant phenotype. Inversely, erlotinib could enhance the 6-P-mediated anticancer activity. Conclusion: Our data indicated that 6-P/EGFR/PI3K/AKT signaling axis might become one of the supplemental therapeutic strategies for pancreatic cancer.

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“…29 PI3K/AKT signaling pathway is involved in cell proliferation, differentiation, apoptosis and other cellular processes. [30][31][32] Meanwhile, the PI3K/AKT signaling pathway takes part in tumor metastasis. 33 Intriguingly, it has been reported that PI3K/ AKT signaling pathway can be regulated by lncRNAs.…”

Section: Discussionmentioning

confidence: 99%

<p>lncRNA TM4SF1-AS1 Activates the PI3K/AKT Signaling Pathway and Promotes the Migration and Invasion of Lung Cancer Cells</p>

Zhou¹,

Wang²,

Chi³

et al. 2020

CMAR

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Metastasis is a crucial cause of the high mortality in patients with lung cancer. Long non-coding RNAs (lncRNAs) are emerging as important players in the development and progression of human cancers. Here, we aimed to identify metastasis-associated lncRNA and to study its roles in the migration and invasion of lung cancer cells. Materials and Methods: We screened differentially expressed lncRNAs between high-and low-metastatic lung cancer cell lines by using microarray and identified the target lncRNA TM4SF1-AS1. The effect of the TM4SF1-AS1 on the invasion and migration was evaluated through the wound healing experiment and transwell assay. The expression of related genes was assessed by RNA sequence and Western blotting. Results: TM4SF1-AS1 was highly expressed in high metastatic lung cancer cell line, and it was also significantly up-regulated in lymph node metastatic lung cancer and was associated with lymph node metastasis. Overexpression of TM4SF1-AS1 promoted the migration and invasion of lung cancer cells. Overexpression of TM4SF1-AS1 decreased the expression of E-Cadherin and increased the expression of Vimentin, Snail and Twist, while knockdown of TM4SF1-AS1 exhibited the opposite trend. Furthermore, RNA sequence analysis revealed that some signaling pathways, including PI3K/AKT signaling pathway, were enriched upon TM4SF1-AS1 overexpression. Western blotting further confirmed that the PI3K/AKT signaling pathway was activated by TM4SF1-AS1. Conclusion: This study illustrates that TM4SF1-AS1 promotes the migration and invasion of lung cancer cells by activating the PI3K/AKT signaling pathway. TM4SF1-AS1 might be a novel target of molecular treatment for lung cancer.

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A novel derivative of valepotriate inhibits the PI3K/AKT pathway and causes Noxa-dependent apoptosis in human pancreatic cancer cells

Cited by 10 publications

References 31 publications

Chrysin Promotes Temozolomide-induced Apoptosis by Activating p38 MAPK and Suppressing Akt and ERK1/2 in Human Glioblastoma.

Chrysin Promotes Temozolomide-induced Apoptosis by Activating p38 MAPK and Suppressing Akt and ERK1/2 in Human Glioblastoma.

[6]-Paradol Suppresses Proliferation and Metastases of Pancreatic Cancer by Decreasing EGFR and Inactivating PI3K/AKT Signaling

<p>lncRNA TM4SF1-AS1 Activates the PI3K/AKT Signaling Pathway and Promotes the Migration and Invasion of Lung Cancer Cells</p>

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