Role of the TLR4-androgen receptor axis and genistein in taxol-resistant ovarian cancer cells

Huang, Shang‐Lang; Chang, Ting‐Chang; Chao, Chuck C.‐K.; Sun, Nian‐Kang

doi:10.1016/j.bcp.2020.113965

Cited by 21 publications

(9 citation statements)

References 55 publications

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“…This observation suggests that paclitaxel‐induced H1.0 protein levels in Txr cells are due to increased mRNA levels, partly via gene transactivation as seen from the observation that H1.0 mRNA stability was not affected by paclitaxel in either cell line. Previous findings showed that the PI3K/AKT pathway is critical for the development of Txr in ovarian cancer 19,20 . We found that AKT phosphorylation was enhanced not only in highly paclitaxel‐resistant SKOV3/Txr cells but also in mildly paclitaxel‐resistant 2774/Txr cells compared with their respective parental cells (Figure 3B).…”

Section: Resultssupporting

confidence: 61%

“…Previous findings showed that the PI3K/AKT pathway is critical for the development of Txr in ovarian cancer. 19,20 We found that AKT phosphorylation was enhanced not only in highly paclitaxel-resistant SKOV3/Txr cells but also in mildly paclitaxelresistant 2774/Txr cells compared with their respective parental cells (Figure 3B). To determine the signaling pathway involved in upregulating H1.0 in paclitaxel-treated SKOV3/Txr cells, we examined H1.0 mRNA and protein expression in the presence of kinase inhibitors, including wortmannin (PI3Ki), SP600125 (JNKi), PD98059 (ERKi), and SB203580 (P38i).…”

Section: Pi3k Is a Critical Upstream Signal Of H10 Expression And Sta...mentioning

confidence: 92%

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H1.0 induces paclitaxel‐resistance genes expression in ovarian cancer cells by recruiting GCN5 and androgen receptor

et al. 2022

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More than 90% of ovarian cancer deaths are due to relapse following development of chemoresistance. Our main objective is to better understand the molecular mechanism underlying paclitaxel resistance (taxol resistance, Txr) in ovarian cancer. Here, we observed that the linker histone H1.0 is upregulated in paclitaxel‐resistant ovarian cancer cells. Knockdown of H1.0 significantly downregulates the androgen receptor (AR) and sensitizes paclitaxel‐resistant SKOV3/Txr and 2774/Txr cell lines to paclitaxel. Conversely, ectopic expression of H1.0 upregulates AR and increases Txr in parental SKOV3 and MDAH2774 cells. Notably, H1.0 upregulation is associated with disease recurrence and poor survival in a subset of ovarian cancer subjects. Inhibition of PI3K significantly reduces H1.0 mRNA and protein levels in paclitaxel‐resistant cells, suggesting the involvement of the PI3K/AKT signaling pathway. Knockdown of H1.0 and AR also downregulates the Txr genes ABCB1 and ABCG2 in paclitaxel‐resistant cells. Our data show that H1.0 induces GCN5 expression and histone acetylation, thereby enhancing Txr gene transactivation. These findings suggest that Txr in ovarian cancer involves the PI3K/AKT pathway and leads to upregulation of histone H1.0, recruitment of GCN5 and AR, followed by upregulation of a subgroup of Txr genes that include ABCB1 and ABCG2 . This study is the first report describing the relationship between histone H1.0 and GCN5 that cooperate to induce AR‐dependent Txr in ovarian cancer cells.

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Section: Resultssupporting

confidence: 61%

Section: Pi3k Is a Critical Upstream Signal Of H10 Expression And Sta...mentioning

confidence: 92%

H1.0 induces paclitaxel‐resistance genes expression in ovarian cancer cells by recruiting GCN5 and androgen receptor

et al. 2022

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“…DCDC2, ANKRD18B, ALDH1A1, c14orf105, ITGBL1, and NEB were related to AR. These six genes were identified as TLR4 and AR-regulated genes involved in txr [ 85 ]. Subsequent studies were performed on overexpressing of TLR4 in OVCA cells treated with paclitaxel.…”

Section: Molecular Biological Characteristics Of a And Armentioning

confidence: 99%

Molecular Regulation of Androgen Receptors in Major Female Reproductive System Cancers

Lian

et al. 2022

IJMS

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There are three main types of cancer in the female reproductive system, specifically ovarian cancer (OVCA), endometrial cancer (EC), and cervical cancer (CC). They are common malignant tumors in women worldwide, with high morbidity and mortality. In recent years, androgen receptors (ARs) have been found to be closely related to the occurrence, progression, prognosis, and drug resistance of these three types of tumors. This paper summarizes current views on the role of AR in female reproductive system cancer, the associations between female reproductive system cancers and AR expression and polymorphisms. AR regulates the downstream target genes transcriptional activity and the expression via interacting with coactivators/corepressors and upstream/downstream regulators and through the gene transcription mechanism of “classical A/AR signaling” or “non-classical AR signaling”, involving a large number of regulatory factors and signaling pathways. ARs take part in the processes of cancer cell proliferation, migration/invasion, cancer cell stemness, and chemotherapeutic drug resistance. These findings suggest that the AR and related regulators could target the treatment of female reproductive system cancer.

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“…On the contrary, ectopic over-expression of ABCB1 blunted the OC cells' response to taxol. Huang et al performed high-throughput transcriptomic analysis and identified androgen receptor (AR) as a taxol resistance associated gene in OC by activating TLR4 (Huang et al, 2020). These findings provide direct evidence that the TLR4/NF-κB induced functional genes might act as novel targets to prevent taxol or other kinds of chemo-resistance (Sun et al, 2018).…”

Section: Tlr4 Contributes To Chemo-resistance and Is Targetable For Ocmentioning

confidence: 99%

The emerging roles of TLR and cGAS signaling in tumorigenesis and progression of ovarian cancer

et al. 2022

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Ovarian cancer is fatal to women and has a high mortality rate. Although on-going efforts are never stopped in identifying diagnostic and intervention strategies, the disease is so far unable to be well managed. The most important reason for this is the complexity of pathogenesis for OC, and therefore, uncovering the essential molecular biomarkers accompanied with OC progression takes the privilege for OC remission. Inflammation has been reported to participate in the initiation and progression of OC. Both microenvironmental and tumor cell intrinsic inflammatory signals contribute to the malignancy of OC. Inflammation responses can be triggered by various kinds of stimulus, including endogenous damages and exogenous pathogens, which are initially recognized and orchestrated by a series of innate immune system related receptors, especially Toll like receptors, and cyclic GMP-AMP synthase. In this review, we will discuss the roles of innate immune system related receptors, including TLRs and cGAS, and responses both intrinsic and exogenetic in the development and treatment of OC.

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Role of the TLR4-androgen receptor axis and genistein in taxol-resistant ovarian cancer cells

Cited by 21 publications

References 55 publications

H1.0 induces paclitaxel‐resistance genes expression in ovarian cancer cells by recruiting GCN5 and androgen receptor

H1.0 induces paclitaxel‐resistance genes expression in ovarian cancer cells by recruiting GCN5 and androgen receptor

Molecular Regulation of Androgen Receptors in Major Female Reproductive System Cancers

The emerging roles of TLR and cGAS signaling in tumorigenesis and progression of ovarian cancer

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