FOXM1 Promotes Drug Resistance in Cervical Cancer Cells by Regulating ABCC5 Gene Transcription

Hou, Youxiang; Zhanfei, Dong; Zhong, Wei; Yin, Linglong; Xiong, Li; Kuerban, Gulina; Huang, He

doi:10.1155/2022/3032590

Cited by 12 publications

(7 citation statements)

References 29 publications

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“…Clinically, chemotherapy is the major therapeutic approach for the conventional and essential treatment of cancer patients [3].Several anti-cancer medicines are being used in the clinic as the primary support of the current treatment to reduce the death of cancer patients [15]. However, inherent or acquired resistance to chemotherapeutic drugs (eg, 5-FU, Cisplatin, Paclitaxel and Carboplatin, Doxorubicin, and Tamoxifen) remains the major contributor to therapy failure in solid cancers [15,16,17,18].Theunderlying mechanisms governing the development of chemoresistance are complicated and the leading pathway(s) are ill-de ned.While multiple mechanisms can mediate drug resistance development, FOXM1 is repeatedly identi ed as a common factor associated with weaker response to conventional cancer therapies by regulating several target genes associated with cell cycle and DNA repair [3,5,18,21,22,23,24].There are diverse molecular mechanisms of cancer drug resistance mediated through FOXM1, including enhanced DNA damage repair [23,24,25], oxidative stress prevention [26,27,28], increased drug e ux activity [29,30,31,20], increased thymidylate synthase (TS) activity [32,33], the negative regulation of the JNK/mitochondrial pathway [34], induction of AMPK/mTOR-mediated autophagy [21], orvia up-regulating microtubule dynamics regulation associated components and blocking drug-induced mitotic catastrophe [35,36].Accordingly, the knockdown of FOXM1 or its downstream targets was found very effective in restoring standard chemotherapy sensitivity in many human cancers, including colorectal cancer [20,32], Lung carcinoma [34], breast cancer [36], ovarian cancer [37], prostate cancer…”

Section: Introductionmentioning

confidence: 99%

WITHDRAWN: Novel FOXM1 inhibitor STL001 sensitizes human cancers to a broad-spectrum of cancer therapies

Gartel,

Raghuwanshi,

Zhang

et al. 2023

Preprint

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Forkhead box protein M1 (FOXM1) is often overexpressed in human cancers and strongly associated with therapy-resistance and less good patient survival. The chemotherapy options for patients with the most aggressive types of solid cancers remain very limited because of the acquired drug-resistance, making the therapy less effective. Pharmacological inhibition of FOXM1 could be a promising approach to sensitize therapy-resistant cancers. Here, we explore a novel FOXM1 inhibitor STL001, a first-generation modification drug of our previously reported FOXM1 inhibitor STL427944. STL001 preserves the mode of action of the STL427944; however, STL001 is up to 50 times more efficient in reducing FOXM1 activity in a variety of solid cancers. The most conventional cancer therapies studied here observed with reduced toxicity due to the induction of FOXM1 expression in solid cancers. Interestingly, STL001 demonstrated suppression of FOXM1 activity and exhibited increased sensitivity of cancer cells to the cytotoxic effects of these drugs. Notably, STL001 does not provide further sensitization to FOXM1-KD cancer cells, suggesting that the sensitization effect is conveyed specifically through FOXM1 suppression. RNA-seq and gene set enrichment studies revealed prominent suppression of FOXM1-dependent pathways and gene ontologies. Also, gene regulation by STL001 showed extensive overlap with FOXM1-KD, suggesting a high selectivity of STL001 toward the FOXM1 regulatory network. A completely new activity of FOXM1, mediated through steroid/cholesterol biosynthetic process and protein secretion in cancer cells was also detected. Collectively, STL001 offers intriguing translational opportunities as combination therapies targeting FOXM1 activity in a variety of human cancers driven by FOXM1.

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Section: Introductionmentioning

confidence: 99%

WITHDRAWN: Novel FOXM1 inhibitor STL001 sensitizes human cancers to a broad-spectrum of cancer therapies

Gartel,

Raghuwanshi,

Zhang

et al. 2023

Preprint

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“…Considering the importance of ABCC5 in drug resistance, additional studies need to be conducted targeting the role of ABCC5. Scholars demonstrated that ABCC5 is an inducer of MDR in human cancer 39,40) . For instance, ABCC5 could affect pemetrexed resistance in breast cancer 41) .…”

Section: Discussionmentioning

confidence: 99%

Upregulation of miR-101-3p Overcomes Ibrutinib Resistance by Targeting ABCC5 in Diffuse Large B-Cell Lymphoma (DLBCL)

Liu

Gao

et al. 2023

J. Hard Tissue Biology.

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Diffuse large B-cell lymphoma (DLBCL) seriously threatens public health, and drug resistance is a formidable obstacle to DLBCL therapy. MicroRNAs (miRNAs) have been certified to act as a momentous regulator in drug resistance of DLBCL. This study aimed to ascertain the latent function and mechanism of miR-101-3p in modulating the resistance of DLBCL cells to ibrutinib. The differentially expressed miRNAs were identified by bioinformatics analysis of GSE117063 and GSE173080 datasets. Quantitative real-time polymerase chain reaction (qRT-PCR) was employed to measure the expression levels of miR-101-3p and ATP-binding cassette subfamily C member 5 (ABCC5). The resistance of DLBCL cells to ibrutinib was determined by 3-(4,5-Dimethylthazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), colony formation, and Western blot assays. The relationship between miR-101-3p expression level and ABCC5 expression level was analyzed using dual-luciferase reporter assay and Pearson correlation test. MiR-101-3p was significantly downregulated in DLBCL cells according to the results of the bioinformatics analysis. A low miR-101-3p expression level predicted resistance of DL-BCL cells to ibrutinib. Upregulation of miR-101-3p sensitized the constructed ibrutinib-resistant DLBCL (DLBCL/ibR). Our findings revealed that ABCC5 was targeted by miR-101-3p, and ABCC5 was abundantly expressed in DLBCL/ibR tissue samples and cells. Furthermore, miR-101-3p mimics overturned the influences of ABCC5 upregulation on the resistance of DLBCL cells to ibrutinib. MiR-101-3p played a suppressive function in the resistance of DLBCL cells to ibrutinib via inhibiting ABCC5 expression, which might represent a potent therapeutic target for DLBCL.

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“…The FOXM1 transcription factor is crucial for cell proliferation, cell cycle control, cell survival, senescence and DNA damage repair [6,12]. Several studies have indicated that high FOXM1 expression enhances chemotherapy resistance in many cancers, including prostate cancer [20], breast cancer [26], and cervical cancer [14]. FOXM1 reg-ulates many cellular processes, for example, DNA repair, cell survival, drug efflux, and deregulated mitosis [12].…”

Section: Discussionmentioning

confidence: 99%

“…FOXM1 is overexpressed in most human cancers, including the cervix, liver, prostate, breast, etc., which indicates a poor prognosis for cancer patients [8,9]. Furthermore, many researchers have found that FOXM1 is closely associated with cancer drug sensitivity, and downregulation of FOXM1 abrogates drug resistance in different cancer cells [10][11][12], including cervical cancer [13,14]. However, the mechanisms of FOXM1 involvement in chemo-treated cervical cancer remain unclear.…”

Section: Introductionmentioning

confidence: 99%

FOXM1 Contributes to Chemotherapy Sensitivity in Cervical Cancer by Regulating TTK

Tang¹,

Xu²,

Yang³

et al. 2023

Discovery Medicine

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Background: The emergence of chemotherapy resistance usually causes therapeutic failure in advanced cervical cancer. Forkhead box protein M1 (FOXM1) and threonine tyrosine kinase (TTK) are closely associated with cancer drug sensitivity, but the mechanism of FOXM1 on TTK involvement in chemo-treated cervical cancer remains unclear. Here, we aimed to observe the effects of FOXM1 on TTK and on chemotherapy sensitivity in cervical cancer. Methods: The expressions of FOXM1 and TTK in cervical cancer tissues and para-cancerous tissues were analyzed by immunohistochemistry. SiHa and Hela cells were transfected with human lentivirus-FOXM1, small interfering RNA (siRNA) or pcDNA3.1/FOXM1 to analyze the changes in TTK protein expression. Furthermore, the cells were treated with paclitaxel (8 µM) or cisplatin (10 µM) to analyze the effects of FOXM1 on chemotherapy sensitivity. SiHa cells were used to construct a xenograft model to study the effects of FOXM1 expression in response to paclitaxel treatment. The tumor size and weight were observed. The expressions of Ki-67, FOXM1, and TTK protein in tumor tissues were measured by immunohistochemistry. Results: High expression of FOXM1 and TTK were found in the cervical cancer tissues (p < 0.05). The TTK protein expressions were decreased by FOMX1-siRNA transfection in SiHa and Hela cells (p < 0.01). The cell viability and cell cycle were also suppressed by FOMX1-siRNA transfection (p < 0.01) but enhanced by pcDNA3.1/FOXM1 transfection (p < 0.01). For paclitaxel or cisplatin treatment, the cell viability and cell DNA damage were improved due to the FOXM1 overexpression (p < 0.01). TTK inhibitor significantly suppressed the effects of FOXM1 overexpression (p < 0.01). Conclusions: FOXM1 regulated TTK and affected the therapeutic efficacy of cisplatin and paclitaxel in cervical cancer.

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FOXM1 Promotes Drug Resistance in Cervical Cancer Cells by Regulating ABCC5 Gene Transcription

Cited by 12 publications

References 29 publications

WITHDRAWN: Novel FOXM1 inhibitor STL001 sensitizes human cancers to a broad-spectrum of cancer therapies

WITHDRAWN: Novel FOXM1 inhibitor STL001 sensitizes human cancers to a broad-spectrum of cancer therapies

Upregulation of miR-101-3p Overcomes Ibrutinib Resistance by Targeting ABCC5 in Diffuse Large B-Cell Lymphoma (DLBCL)

FOXM1 Contributes to Chemotherapy Sensitivity in Cervical Cancer by Regulating TTK

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