Inhibition of autophagy by 3-MA enhances IL-24-induced apoptosis in human oral squamous cell carcinoma cells

Li, Jichen; Yang, Dezhao; Wang, Wei; Piao, Shilong; Zhou, Jianyu; Saiyin, Wuliji; Zheng, Changyu; Sun, Hongchen; Yu, Li

doi:10.1186/s13046-015-0211-0

Cited by 43 publications

(35 citation statements)

References 27 publications

(22 reference statements)

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“…4A). Using the autophagy inhibitor 3-methyladenine (20), similar, but less pronounced proliferation effects were seen in both B16 and ID8agg cells (data not shown).…”

Section: Resultsmentioning

confidence: 83%

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Tumor-Intrinsic PD-L1 Signals Regulate Cell Growth, Pathogenesis, and Autophagy in Ovarian Cancer and Melanoma

et al. 2016

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PD-L1 antibodies produce efficacious clinical responses in diverse human cancers, but the basis for their effects remains unclear, leaving a gap in understanding of how to rationally leverage the therapeutic activity. PD-L1 is widely expressed in tumor cells but its contributions to tumor pathogenicity are incompletely understood. In this study, we evaluated the hypothesis that PD-L1 exerts tumor cell-intrinsic signals that are critical for pathogenesis. Using RNAi methodology, we attenuated PD-L1 in the murine ovarian cell line ID8agg and the melanoma cell line B16 (termed PD-L1lo cells), which express basal PD-L1. We observed that PD-L1lo cells proliferated more weakly than control cells in vitro. As expected, PD-L1lo cells formed tumors in immunocompetent mice relatively more slowly, but unexpectedly, they also formed tumors more slowly in immunodeficient NSG mice. A comparative microarray analysis identified a number of genes involved in autophagy and mTOR signaling that were affected by PD-L1 expression. In support of a functional role, PD-L1 attenuation augmented autophagy and blunted the ability of autophagy inhibitors to limit proliferation in vitro and in vivo in NSG mice. PD-L1 attenuation also elevated mTORC1 activity and augmented the anti-proliferative effects of the mTORC1 inhibitor rapamycin. PD-L1 cells were also relatively deficient in metastasis to the lung and we found that anti-PD-L1 administration could block tumor cell growth and metastasis in NSG mice. This therapeutic effect was observed with B16 cells but not ID8agg cells, illustrating tumor- or tissue-specific effects in the therapeutic setting. Overall, our findings extend understanding of PD-L1 functions, illustrate non-immune effects of anti-PD-L1 immunotherapy and suggest broader uses for PD-L1 as a biomarker for assessing cancer therapeutic responses.

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“…4A). Using the autophagy inhibitor 3-methyladenine (20), similar, but less pronounced proliferation effects were seen in both B16 and ID8agg cells (data not shown).…”

Section: Resultsmentioning

confidence: 83%

“…For pharmacologic autophagy inhibition in vivo , mice were injected intraperitoneally with chloroquine 60 mg/kg every other day (18,19) or 3-methyladenine 25 mg/kg every 5 days (20) versus PBS control starting on day 7 following tumor challenge, regimens shown to inhibit tumor cell autophagy effectively in vivo .…”

Section: Methodsmentioning

confidence: 99%

Tumor-Intrinsic PD-L1 Signals Regulate Cell Growth, Pathogenesis, and Autophagy in Ovarian Cancer and Melanoma

et al. 2016

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“…In order to further confirm the role of IL-17/IL-17R and the JAK2/STAT3 signaling pathway in the induction of autophagy and inhibition of apoptosis, SMMC-7721 cells were treated with 3-methyladenine (3-MA; 10 mM; Sigma-Aldrich; Merck Millipore), which is a known inhibitor of autophagy (41), and AG490 to inhibit the JAK2/STAT3 signaling pathway. Compared with the cells treated with oxaliplatin only, the AG490-and oxaliplatin-treated cells expressed less BCL-2 and more BAX, which indicated that apoptosis was induced to a greater extent in these cells.…”

Section: Il-17/il-17r Induces Autophagy In Smmc-7721 Cells Throughmentioning

confidence: 99%

Autophagy impacts on oxaliplatin-induced hepatocarcinoma apoptosis via the IL-17/IL-17R-JAK2/STAT3 signaling pathway

Guo

Cao

et al. 2016

Oncology Letters

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Abstract. The interleukin (IL)-17/IL-17 receptor (IL-17R)complex has been shown to be important for the regulation of inflammation; however, its role in the regulation of tumor processes has recently emerged as a research focus. The present study demonstrated that oxaliplatin was able to increase the levels of IL-17/IL-17R in hepatocellular carcinoma (HCC) patients and cells lines, and that it had important roles in reducing the susceptibility of the cells to oxaliplatin-induced apoptosis. Furthermore, the expression of autophagy-related proteins was induced by IL-17/IL-17R and autophagy was shown to induce resistance to oxaliplatin in HCC. In addition, the janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway was shown to be an important pathway in the induction of autophagy in response to oxaliplatin. Autopjhagy was inhibited by 3-methyladenine and JAK2/STAT3 signaling was blocked by AG490, which induced apoptosis in SMMC7721 cells treated with oxaliplatin. The results of the present study may help to elucidate the mechanism underlying the role of IL-17/IL-17R-induced autophagy in the chemoresistance of HCC, as well as help to establish and develop measures to overcome chemoresistance in HCC. IntroductionHepatocellular carcinoma (HCC) is a major malignancy worldwide and its incidence is increasing annually; it is the second most common cause of cancer-associated mortality (1).The majority of patients have a low survival rate as a result of locally advanced or metastatic diseases, and surgery is feasible for only a small percentage of patients with HCC. Therefore, chemotherapy is the optimal therapeutic strategy for inoperable HCC (2). Oxaliplatin has been widely used in chemotherapy to reduce tumor recurrence and prolong survival in patients with HCC because of its fewer side effects compared with other platinum drugs (3). However, chemoresistance to oxaliplatin in the form of suppressed HCC apoptosis is commonly observed (4).Interleukin-17 (IL-17) is predominantly secreted by interleukin-17-producing T-helper (Th17) cells, which participate in the progression and pathogenesis of inflammatory diseases (3). The IL-17 receptor (IL-17R) is expressed on the surface of numerous cells, including macrophages, dendritic cells, epithelial cells, fibroblasts and T lymphocytes (5,6). Previous studies reported that IL-17-producing cells accumulated in tumors (7,8), and that patients with malignant serum effusions (9) or multiple myeloma (10) showed significantly higher serum levels of IL-17. Furthermore, patients with persistently higher levels of IL-17 demonstrated the requirement for longer courses of chemotherapy, since these patients comprised a significant proportion of all cases of recurrence (11). Typically, IL-17 does not engage with Toll/IL-1 receptor (TIR) domain-containing adaptors, such as MyD88, TIR domain-containing adapter protein inducing interferon-β or IL-1 receptor-associated kinases (12). Rather, IL-17 signals through nuclear factor (NF)-κB (13), mitogen-activated pro...

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“…IL-24 expression is lost in most cancer cells of human origin [2][3][4]. Studies have shown that loss of IL-24 expression is correlated with disease progression in prostate cancer [5], breast cancer [6], colon cancer [7], neuroblastoma [8], acute leukemia [9], oral squamous cell carcinoma [10,11], lung cancer [12] and other cancers [13][14][15][16][17]. Exogenous IL-24 expression has anti-tumor, anti-angiogenic and anti-metastatic properties and suppresses various signaling pathways, without harming normal cells [2][3][4][5].…”

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confidence: 99%

miR‐203a‐3p.1 targets IL‐24 to modulate hepatocellular carcinoma cell growth and metastasis

Huo

Pan

et al. 2017

FEBS Open Bio

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Hepatocellular carcinoma ( HCC ) is one of the most common causes of cancer‐related death. Cytokines, including interleukin 24 ( IL ‐24), play an important role in HCC . IL ‐24 inhibits HCC metastasis but the molecular mechanism by which this occurs is still unknown. Micro RNA s (mi RNA s) are regulators of cancers including hepatocellular carcinoma ( HCC ). However, the role that mi RNA s play in the regulation of IL ‐24 in HCC is unclear. The aim of this study was to investigate the effects of regulation of IL‐24 by miR‐203a‐3p.1 on liver cancer cell proliferation and metastasis. IL ‐24 mRNA and miR‐203a‐3p.1 were detected by real‐time RT ‐ PCR , and IL ‐24 protein in the cell growth medium was measured by ELISA . A luciferase assay was used to verify that the IL ‐24 gene was the target of miR‐203a‐3p.1. Cell survival ability was detected by the MTT assay and colony formation. Cell metastasis was assayed by the Transwell system. The results showed that IL ‐24 could be down‐regulated by miR‐203a‐3p.1 in HCC cells and that miR‐203a‐3p.1 acted as an onco‐mi RNA by targeting IL ‐24. Inhibition of miR‐203a‐3p.1 in cells could lead to the reversal of HCC cell proliferation and metastasis. The study highlights a novel molecular interaction between miR‐203a‐3p.1 and IL ‐24, which indicates that IL ‐24 and miR‐203a‐3p.1 may constitute potential therapeutic targets for HCC .

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Inhibition of autophagy by 3-MA enhances IL-24-induced apoptosis in human oral squamous cell carcinoma cells

Cited by 43 publications

References 27 publications

Tumor-Intrinsic PD-L1 Signals Regulate Cell Growth, Pathogenesis, and Autophagy in Ovarian Cancer and Melanoma

Tumor-Intrinsic PD-L1 Signals Regulate Cell Growth, Pathogenesis, and Autophagy in Ovarian Cancer and Melanoma

Autophagy impacts on oxaliplatin-induced hepatocarcinoma apoptosis via the IL-17/IL-17R-JAK2/STAT3 signaling pathway

miR‐203a‐3p.1 targets IL‐24 to modulate hepatocellular carcinoma cell growth and metastasis

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