Atractylenolide-I Sensitizes Human Ovarian Cancer Cells to Paclitaxel by Blocking Activation of TLR4/MyD88-dependent Pathway

Huang, Jianming; Zhang, Guonan; Shi, Yu; Zha, Xiao; Zhu, Yi; Wang, Miaomiao; Lin, Qing; Wang, Wen; Lu, Haiyan; Ma, Sai; Cheng, Jing; Deng, Bi-Fang

doi:10.1038/srep03840

Cited by 54 publications

(46 citation statements)

References 39 publications

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“…In the present study, we provided evidence demonstrating the anti-lung cancer effects of ATL-l. The doses of ATL-1 in the current study were similar or even lower than those reported by others demonstrating substantial anti-cancer responses in several cancer types [13, 45, 49]. Our results showed that ATL-1 inhibited lung cancer cell growth through ERK1/2-mediated suppression of Stat3 and SP1 protein expressions.…”

Section: Discussionmentioning

confidence: 41%

Activation of ERK and Mutual Regulation of Stat3 and SP1 Contribute to Inhibition of PDK1 Expression by Atractylenolide-1 in Human Lung Cancer Cells

Xiao¹,

Zheng²,

Wu³

et al. 2017

Cell Physiol Biochem

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Background/Aims: Atractylodes macrocephula Koidz is an important ingredient in traditional Chinese herbs. One major bioactive compound, atractylenolide-1 (ATL-1), was reported to have anti-inflammatory and anti-tumor activities. However, the underlying molecular mechanism associated to this has not been well elucidated. Methods: Cell viability and cell cycle distribution were measured using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) and flow cytometry assays, respectively. Western blot analysis was performed to examine the phosphorylation and protein expression of extracellular signaling-regulated kinase 1/2 (ERK1/2), signal transducer and activator of transcription 3 (Stat3), 3-phosphoinositide dependent protein kinase-1 (PDK1) and transcription factor SP1. QRT-PCR was used to examine the mRNA levels of PDK1 gene. Exogenously expressions of Stat3, PDK1 and SP1 were carried out by transient transfection assays. PDK1 promoter activity was measured by Secrete-Pair Dual Luminescence Assay Kit. A nude mice xenograft model was used to confirm the findings in vitro. Results: We showed that ATL-1 inhibited human lung cancer cell growth and induced cell cycle arrest. Furthermore, we found that ATL-1 stimulated phosphorylation of ERK1/2, inhibited phosphorylation and protein expressions of Stat3 and SP1; the latter were abrogated in the presence of MEK/ERK inhibitor PD98059. Moreover, ATL-1 reduced the protein, mRNA expression and promoter activity of PDK1. Intriguingly, exogenously expressed Stat3 and SP1 overcame ATL-1-inhibited SP1 and Stat3, and PDK1 protein expressions, respectively. Moreover, overexpression of PDK1 resisted the ATL-1-inhibited lung cancer cell growth. In consistent with the results in vitro, ATL-1 inhibited tumor growth, protein expressions of Stat3, SP1 and PDK1, and induced phosphorylation of ERK1/2 in vivo. Conclusion: In summary, our results show that ATL-1 inhibits lung cancer cell growth through activation of ERK1/2, followed by suppressing SP1 protein expression. ATL-1 also reduces phosphorylation and protein levels of Stat3. These are mutual regulation between Stat3 and SP1 proteins affected by ATL-1. This ultimately suppresses PDK1 gene expression. This study reveals a novel mechanism by which ATL-1 inhibits growth of lung cancer cells. Thus, targeting PDK1 pinpoints a potential in the lung cancer treatment.

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Section: Discussionmentioning

confidence: 41%

Activation of ERK and Mutual Regulation of Stat3 and SP1 Contribute to Inhibition of PDK1 Expression by Atractylenolide-1 in Human Lung Cancer Cells

Xiao¹,

Zheng²,

Wu³

et al. 2017

Cell Physiol Biochem

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“…TLR4 also has been identified at the protein level in breast epithelial tumor cells (5). In contrast to its role in tumor-associated immune cells, TLR4 promotes growth (6) and chemotherapeutic resistance (7,8) in ER-negative breast cancer cell lines, in accordance with studies of ovarian cancer (9,10). Based on these studies, therapies targeting TLR4 appear to be novel viable strategies with significant potential for treating cancer, and have in fact been proposed as such (6)(7)(8).…”

mentioning

confidence: 72%

TLR4 has a TP53-dependent dual role in regulating breast cancer cell growth

Haricharan

Brown

2015

Proc. Natl. Acad. Sci. U.S.A.

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Breast cancer is a leading cause of cancer-related death, and it is important to understand pathways that drive the disease to devise effective therapeutic strategies. Our results show that Toll-like receptor 4 (TLR4) drives breast cancer cell growth differentially based on the presence of TP53, a tumor suppressor. TP53 is mutationally inactivated in most types of cancer and is mutated in 30-50% of diagnosed breast tumors. We demonstrate that TLR4 activation inhibits growth of TP53 wild-type cells, but promotes growth of TP53 mutant breast cancer cells by regulating proliferation. This differential effect is mediated by changes in tumor cell cytokine secretion. Whereas TLR4 activation in TP53 mutant breast cancer cells increases secretion of progrowth cytokines, TLR4 activation in TP53 wild-type breast cancer cells increases type I IFN (IFN-γ) secretion, which is both necessary and sufficient for mediating TLR4-induced growth inhibition. This study identifies a novel dichotomous role for TLR4 as a growth regulator and a modulator of tumor microenvironment in breast tumors. These results have translational relevance, demonstrating that TP53 mutant breast tumor growth can be suppressed by pharmacologic TLR4 inhibition, whereas TLR4 inhibitors may in fact promote growth of TP53 wild-type tumors. Furthermore, using data generated by The Cancer Genome Atlas consortium, we demonstrate that the effect of TP53 mutational status on TLR4 activity may extend to ovarian, colon, and lung cancers, among others, suggesting that the viability of TLR4 as a therapeutic target depends on TP53 status in many different tumor types.reast cancer has one of the highest incidence rates of cancer in women worldwide, with more than 1.5 million women diagnosed with the disease in 2012. Owing to its high incidence, breast cancer is also one of the leading causes of cancer-related deaths, with 40,000 women predicted to die of the disease in 2014 in the US alone. The diagnosis and treatment of breast cancer has been significantly improved by the identification of three major subtypes of the disease based on receptor expression: estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-positive, and triple-negative [tumors lacking ER, progesterone receptor (PR), and HER2]. Of these subtypes, ER-positive breast cancer accounts for 70-80% of all diagnosed breast tumors.ER-positive breast cancer is largely responsive to endocrine therapy; however, intrinsic or acquired resistance occurs in onethird of cases and contributes significantly to breast cancerassociated mortality. Therefore, identifying therapeutic targets to prevent ER-positive breast cancer mortality is a major focus of scientific investigation. ER-positive breast tumors with a high mutation load are associated with poor patient survival, and a high mutation load likely affects the response to endocrine therapy (1). Because known drivers of endocrine resistance (e.g., PR negativity and HER2 amplification) are not enriched in this subset, the identification of no...

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“…and exerts a wide range of pharmacological activities, including anti-inflammatory (11,12), anti-tumor (13,14) and anti-angiogenic effects (15). A previous study has implied a potential anti-depressive activity of AT-I (16).…”

Section: Introductionmentioning

confidence: 99%

Anti-depressant-like effect of atractylenolide I in a mouse model of depression induced by chronic unpredictable mild stress

Gao

Zhu

et al. 2017

Exp Ther Med

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Abstract. Atractylenolide I (AT-I), a major component of the rhizoma of Atractylodes macrocephala Koidz., exerts a wide range of activities. The purpose of the present study was to investigate the anti-depressant-like effect of AT-I in a mouse model of chronic unpredictable mild stress (CUMS), and to explore the possible molecular mechanism involved. It was revealed that AT-I significantly ameliorated CUMS-induced depressive-like behaviors, as evidenced by increased sucrose preference as well as shortened immobility time in the forced swimming and the tail suspension test. In addition, AT-I reduced CUMS-induced decreases in the concentrations of serotonin and norepinephrine in the hippocampus. Furthermore, AT-I inhibited the activation of the nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome as well as the concentration of the pro-inflammatory cytokine interleukin (IL)-1β in the hippocampi of mice subjected to CUMS. In conclusion, the results of the present study suggested that AT-I exerts anti-depressant-like effects in a CUMS-induced model of depression in mice, the molecular mechanism of which is associated with the inhibition of NLRP3 inflammasome activation to decrease IL-1β production.

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Atractylenolide-I Sensitizes Human Ovarian Cancer Cells to Paclitaxel by Blocking Activation of TLR4/MyD88-dependent Pathway

Cited by 54 publications

References 39 publications

Activation of ERK and Mutual Regulation of Stat3 and SP1 Contribute to Inhibition of PDK1 Expression by Atractylenolide-1 in Human Lung Cancer Cells

Activation of ERK and Mutual Regulation of Stat3 and SP1 Contribute to Inhibition of PDK1 Expression by Atractylenolide-1 in Human Lung Cancer Cells

TLR4 has a TP53-dependent dual role in regulating breast cancer cell growth

Anti-depressant-like effect of atractylenolide I in a mouse model of depression induced by chronic unpredictable mild stress

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