NUPR1 Silencing Induces Autophagy-Mediated Apoptosis in Multiple Myeloma Cells Through the PI3K/AKT/mTOR Pathway

Li, Anmao; Li, Xingxin; Chen, Xuanxin; Zeng, Chensi; Wang, Zuo; Li, Zhen; Chen, Jianbin

doi:10.1089/dna.2019.5196

Cited by 28 publications

(29 citation statements)

References 27 publications

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“…Zhou et al pointed out that overexpressed NUPR1 can weaken the inhibitory effects of miR-4443 on osteosarcoma cell metastasis (35) activates PI3K/AKT, thus affecting tumor progression. For instance, NUPR1 silencing induced autophagy-induced apoptosis of multiple myeloma cells via the PI3K/AKT/ mTOR pathway (36). In the present study, we confirmed through in vitro experiments that NUPR1 was upregulated in OSCC, which is consistent with previous studies (17).…”

Section: Discussionsupporting

confidence: 92%

CircRNA HIPK3 promotes the progression of oral squamous cell carcinoma through upregulation of the NUPR1/PI3K/AKT pathway by sponging miR-637

Jiang¹,

Zhang²,

Zhang³

et al. 2021

Ann Transl Med

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Background: To investigate the expression, function, and related mechanisms of circHIPK3 in oral squamous cell carcinoma (OSCC). Methods: CircHIPK3 expression was determined by quantitative reverse transcription polymerized chain reaction (QRT-PCR) in OSCC and adjacent tissues, and the correlation between the circHIPK3 level and clinicopathological indexes of OSCC was analyzed. CircHIPK3 expressions in different OSCC cell lines were detected, cell counting kit-8 (CCK-8) and 5-bromodeoxyuridine (BrdU) assays were utilized to monitor cell proliferation and activity. Flow cytometry was adopted to detect apoptosis and transwell assay was used to detect cell invasion. The expressions of nuclear protein 1 (NUPR1), phosphatidylinositol 3 kinase (PI3K)/ protein kinase B (AKT) (PI3K/AKT) pathway proteins, and E-cadherin, Vimentin, and N-cadherin markers of epithelial-mesenchymal transformation (EMT) were detected by Western blot or Quantitative Real-time PCR (QRT-PCR).Results: Upregulated circHIPK3 was noted in OSCC tissues (compared with adjacent tissues), and its overexpression was related to OSCC size and histopathological grade. Functionally, overexpressed circHIPK3 can significantly promote EMT, proliferation, and invasion of OSCC cells and can inhibit cell apoptosis in vivo and in vitro. In addition, CircHIPK3 upregulated the activation of NUPR1 and PI3K/AKT. Bioinformatics analyses showed that miR-637 was the common target of circHIPK3 and NUPR1, while a dual luciferase reporting assay and RIP assay further demonstrated that circHIPK3 targeted miR-637 and bound to 3' UTR of NUPR1.Conclusions: CircHIPK3 demonstrates potential as a prognostic marker of OSCC and mediates OSCC progression via the miR-637-mediated NUPR1/PI3K/AKT axis.

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Section: Discussionsupporting

confidence: 92%

CircRNA HIPK3 promotes the progression of oral squamous cell carcinoma through upregulation of the NUPR1/PI3K/AKT pathway by sponging miR-637

Jiang¹,

Zhang²,

Zhang³

et al. 2021

Ann Transl Med

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“…We found that the depletion of NUPR1 or LCN2 had a similar pro-ferroptotic phenotype in human or mouse PDACs, whereas re-expression of LCN2 reversed the exaggerated ferroptosis observed in Nupr1 −/− cells. Combined with other studies on models of apoptosis 31,48 , necroptosis 28,44 and autophagy-dependent cell death 41,49,50 , the present study suggests that the activation of NUPR1 may play a universal cytoprotective role. Since ATF4 has been shown to promote the expression of solute carrier family 7 member 11 (SLC7A11, a component of the antiporter system xc − that inhibits ferroptosis by importing the amino acid cystine for glutathione production in cells) 21 , it is necessary to investigate whether NUPR1 is also involved in ATF4-mediated SLC7A11 expression in the future.…”

Section: Discussionsupporting

confidence: 81%

NUPR1 is a critical repressor of ferroptosis

et al. 2021

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Ferroptosis is a type of iron-dependent regulated cell death, representing an emerging disease-modulatory mechanism. Transcription factors play multiple roles in ferroptosis, although the key regulator for ferroptosis in iron metabolism remains elusive. Using NanoString technology, we identify NUPR1, a stress-inducible transcription factor, as a driver of ferroptosis resistance. Mechanistically, NUPR1-mediated LCN2 expression blocks ferroptotic cell death through diminishing iron accumulation and subsequent oxidative damage. Consequently, LCN2 depletion mimics NUPR1 deficiency with respect to ferroptosis induction, whereas transfection-enforced re-expression of LCN2 restores resistance to ferroptosis in NUPR1-deficient cells. Pharmacological or genetic blockade of the NUPR1-LCN2 pathway (using NUPR1 shRNA, LCN2 shRNA, pancreas-specific Lcn2 conditional knockout mice, or the small molecule ZZW-115) increases the activity of the ferroptosis inducer erastin and worsens pancreatitis, in suitable mouse models. These findings suggest a link between NUPR1-regulated iron metabolism and ferroptosis susceptibility.

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“…Next, in order to verify whether SMBJD exerts its anticancer effect via modulation of autophagy, the expression of LC3-II/ LC3-I, which indicates the level of autophagy, was tested in tumor tissues; it was downregulated after SMBJD treatment (Wang et al, 2008;Runwal et al, 2019), whereas P62, which forms a complex with LC3-II and is then degraded in the lysosome in the late stage of autophagy, increased after SMBJD treatment (Bjorkoy et al, 2005). Accumulation of P62 results in either a reduction in autophagy activity or a block in the combination of autophagosome and lysosome (Li et al, 2020). Thus, these results indicate that SMBJD can inhibit the autophagy process.…”

Section: Discussionmentioning

confidence: 79%

Shengma Biejia Decoction Inhibits Cell Growth in Multiple Myeloma by Inducing Autophagy-Mediated Apoptosis Through the ERK/mTOR Pathway

Dai

et al. 2021

Front. Pharmacol.

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Shengma Biejia decoction (SMBJD), a traditional Chinese formula recorded in the Golden Chamber, has been widely used for the treatment of malignant tumors. However, its underlying molecular targets and mechanisms are still unclear. This study showed that SMBJD inhibited tumor growth and stimulated hemogram recovery significantly in a multiple myeloma xenograft model. Western blot and immunohistochemistry assays of tumor tissues showed that SMBJD reduced the ratio of autophagy-related proteins LC3-II/LC3-I, while P62 and apoptosis-related proteins cleaved caspase-3/caspase-3 and Bax/Bcl-2 were upregulated. In vitro experiments demonstrated the time-dependent and dose-dependent cytotoxicity of SMBJD on multiple myeloma cell lines H929 and U266 through MTT assays. The LC3-II/LC3-I ratio and number of GFP-LC3 puncta showed that SMBJD inhibited the autophagy process of H929 and U266 cells. Moreover, both SMBJD and 3-methyladenine (3-MA) caused a decrease in LC3-II/LC3-I, and SMBJD could not reverse the upregulation of LC3-II/LC3-I caused by bafilomycin A1 (Baf-A1). Furthermore, the results of annexin V-FITC and propidium iodide double staining demonstrated that SMBJD treatment induced the apoptosis of H929 and U266 cells. These data prove that SMBJD inhibits autophagy and promotes apoptosis in H929 and U266 cells. The results also show that rapamycin could reduce the rate of SMBJD-induced apoptosis in H929 and U266 cells, at a concentration which had no effect on apoptosis but activated autophagy. In addition, analysis of the mechanism indicated that levels of phosphorylated ERK and phosphorylated mTOR were increased by treatment with SMBJD in vivo and in vitro. These results indicate that SMBJD, an old and effective herbal compound, could inhibit the viability of H929 and U266 cells and induce autophagy-mediated apoptosis through the ERK/mTOR pathway. Thus, it represents a potential therapy strategy for multiple myeloma.

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NUPR1 Silencing Induces Autophagy-Mediated Apoptosis in Multiple Myeloma Cells Through the PI3K/AKT/mTOR Pathway

Cited by 28 publications

References 27 publications

CircRNA HIPK3 promotes the progression of oral squamous cell carcinoma through upregulation of the NUPR1/PI3K/AKT pathway by sponging miR-637

CircRNA HIPK3 promotes the progression of oral squamous cell carcinoma through upregulation of the NUPR1/PI3K/AKT pathway by sponging miR-637

NUPR1 is a critical repressor of ferroptosis

Shengma Biejia Decoction Inhibits Cell Growth in Multiple Myeloma by Inducing Autophagy-Mediated Apoptosis Through the ERK/mTOR Pathway

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