Zoledronic acid inhibits the growth of cancer stem cell derived from cervical cancer cell by attenuating their stemness phenotype and inducing apoptosis and cell cycle arrest through the Erk1/2 and Akt pathways

Wang, Li; Liu, Yanyang; Zhou, Yongfang; Wang, Jiantao; Tu, Li; Sun, Zhen; Wang, Xiu‐Jie; Luo, Feng

doi:10.1186/s13046-019-1109-z

Cited by 48 publications

(49 citation statements)

References 54 publications

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“…Interestingly, western blotting and immunohistochemistry analysis showed that carbon-ion beam irradiation combined with ZOL upregulated the expression of EMT markers such as E-cadherin but downregulated vimentin. Our findings are consistent with those of previous reports, which stated that ZOL exhibits antitumor and antimetastatic activities [25,32,43,44].…”

Section: Discussionsupporting

confidence: 94%

Carbon-Ion Beam Irradiation Alone or in Combination with Zoledronic acid Effectively Kills Osteosarcoma Cells

Kim

Takahashi

et al. 2020

Cancers

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Osteosarcoma (OSA) is the most common malignant bone tumor in children and adolescents. The overall five-year survival rate for all bone cancers is below 70%; however, when the cancer has spread beyond the bone, it is about 15-30%. Herein, we evaluated the effects of carbon-ion beam irradiation alone or in combination with zoledronic acid (ZOL) on OSA cells. Carbon-ion beam irradiation in combination with ZOL significantly inhibited OSA cell proliferation by arresting cell cycle progression and initiating KHOS and U2OS cell apoptosis, compared to treatments with carbon-ion beam irradiation, X-ray irradiation, and ZOL alone. Moreover, we observed that this combination greatly inhibited OSA cell motility and invasion, accompanied by the suppression of the Pi3K/Akt and MAPK signaling pathways, which are related to cell proliferation and survival, compared to individual treatments with carbon-ion beam or X-ray irradiation, or ZOL. Furthermore, ZOL treatment upregulated microRNA (miR)-29b expression; the combination with a miR-29b mimic further decreased OSA cell viability via activation of the caspase 3 pathway. Thus, ZOL-mediated enhancement of carbon-ion beam radiosensitivity may occur via miR-29b upregulation; co-treatment with the miR-29b mimic further decreased OSA cell survival. These findings suggest that the carbon-ion beam irradiation in combination with ZOL has high potential to increase OSA cell death.Cancers 2020, 12, 698 2 of 15 increasing amount of evidence has demonstrated that high linear energy transfer (LET) carbon-ion radiation therapy is suitable for targeting many kinds of radioresistant tumors such as those associated with bone and soft tissue malignancies including OSA [9][10][11][12][13][14] because it primarily does not elicit cell cycle-and oxygen-dependent cell-killing effects; it also has a high potential to kill radiochemo-resistant cancer stem cells (CSCs) compared to low LET radiation [15][16][17][18][19]. However, although carbon ion beam radiotherapy treatment has yielded promising results, the prognosis of OSA still remains unsatisfactory; developing novel combinational therapeutic strategies to further improve overall survival is required.Bisphosphonates comprise the most important class of osteoclast-mediated bone resorption inhibitors and are used extensively for treating skeletal diseases such as postmenopausal osteoporosis and tumor-induced osteolysis [20,21]. Zoledronic acid (ZOL), a third-generation nitrogen-containing bisphosphonate, is an inhibitor of osteoclast-mediated bone resorption that has demonstrated efficacy in treating bone metastases in cancer patients with breast, prostate, lung, and other solid tumors [22][23][24]. ZOL significantly enhances radiation-induced apoptosis and decreases cell viability, suggesting that it may exhibit radiosensitizing effects [25][26][27][28][29][30][31][32][33]. We have previously reported that ZOL enhanced γ-ray radiation-induced DNA damage and suppressed OSA cell migration and invasion [34,35]. Recently, we also found that it signi...

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Section: Discussionsupporting

confidence: 94%

Carbon-Ion Beam Irradiation Alone or in Combination with Zoledronic acid Effectively Kills Osteosarcoma Cells

Kim

Takahashi

et al. 2020

Cancers

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“…The expression of ALDH1 is also associated with neurogenic locus notch homolog 3 (28), transforming growth factor-β (29) and nuclear factor-κB (30) signaling pathways. In cervical cancer, the expression of ALDH1 is closely related to the Erk1/2 and Akt signaling pathways (31). Based on these data, it is hypothesized that high expression of ALDH1 contributes to drug resistance in cervical cancer.…”

Section: Discussionmentioning

confidence: 99%

Aldehyde dehydrogenase 1, a target of miR‑222, is expressed at elevated levels in cervical cancer

et al. 2020

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The aim of the present study was to investigate the expression of microRNA-222 (miR-222) and aldehyde dehydrogenase 1 (ALDH1) in tissues and peripheral blood of cervical cancer patients, and to elucidate their underlying mechanisms of action. Tumor tissues and tumor-adjacent tissues were obtained from 33 cervical cancer patients and peripheral blood was obtained from these patients and 28 healthy subjects. The expression of miR-222 and ALDH1 mRNA was evaluated by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). To examine the levels of ALDH1 protein in tissues and blood, western blotting and ELISA were used. To confirm a direct interaction between miR-222 and ALDH1 mRNA, a dual luciferase reporter assay was performed. HeLA cells were transfected with agomiR-222 and expression of ALDH1 in the cells was measured by RT-qPCR and western blotting. MTT assay was preform to investigate the proliferation of HeLA cells. Expression of ALDH1 mRNA and protein was elevated in cervical cancer tissues and peripheral blood from patients compared with tumor-adjacent tissues and healthy controls, while the expression of miR-222 was reduced. Upregulation of miR-222 inhibited HeLA cell proliferation possibly due to a reduction in the expression of ALDH1. A dual luciferase reporter assay showed that miR-222 can bind with the 3'-untranslated seed region of ALDH1 mRNA to regulate its expression. miR-222 regulation of ALDH1 expression may play a role in the prevention of cervical cancer.

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“…Cancer stemness has been one of the most important potential mechanisms leading to CRC tumourigenesis and progression (22). To elucidate whether TM4SF1 is associated with the stem cell-like properties of CRC cells, we performed a sphere formation assay and found that knockdown of TM4SF1 expression signi cantly decreased the sphere formation and TM4SF1 overexpression enhanced sphere formation capability of both cell lines ( Fig.…”

Section: Tm4sf1 Promotes Cell Migration Invasion and Proliferation Imentioning

confidence: 99%

“…Cancer stem cells (CSCs) are capable of self-renewal, asymmetric cell division, resistance to apoptosis, tumourigenicity and high metastatic potential (20,21). Abundant evidence indicates that CSCs are involved in tumour invasion, metastasis, and radiotherapy or chemotherapy-induced resistance (22,23). In addition, accumulating studies have revealed that EMT plays an important role in the enrichment of cells with CSC properties, which is believed to be the origin of cancer progression.…”

Section: Introductionmentioning

confidence: 99%

TM4SF1 promotes EMT and cancer stemness via the Wnt/β-catenin/SOX2 pathway in colorectal cancer

Tang

Chen

et al. 2020

Preprint

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Background: Transmembrane 4 L six family member 1 (TM4SF1) is upregulated in several epithelial cancers and is closely associated with poor prognosis. However, the role of TM4SF1 and its potential mechanism in colorectal cancer (CRC) remain elusive.Methods: We investigated the expression of TM4SF1 in the Oncomine, the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases and confirmed the results by immunohistochemistry (IHC), qPCR and Western blotting (WB) of CRC tissues. The effect of TM4SF1 on the epithelial-to-mesenchymal transition (EMT) and cancer stemness of CRC cells was investigated by Transwell, wound healing and sphere formation assays. A series of in vitro and in vivo experiments were conducted to reveal the mechanisms by which TM4SF1 modulates EMT and cancer stemness in CRC.Results: TM4SF1 expression was markedly higher in CRC tissues than in non-tumour tissues and was positively correlated with poor prognosis. Downregulation of TM4SF1 inhibited the migration, invasion and tumour sphere formation of SW480 and LoVo cells. Conversely, TM4SF1 overexpression significantly enhanced the migration, invasion and tumoursphere formation potential of CRC cells, Additionally, TM4SF1 silencing inhibited the EMT mediated by transforming growth factor-β1 (TGF-β1). Mechanistically, gene set enrichment analysis (GSEA) predicted that the Wnt signalling pathway was one of the most impaired pathways in TM4SF1-deficient CRC cells compared to controls. The results were further validated by WB, which revealed that TM4SF1 modulated SOX2 expression in a Wnt/β-catenin activation-dependent manner. Furthermore, we found that knockdown of TM4SF1 suppressed the expression of c-Myc, leading to decreased c-Myc binding to the SOX2 gene promoter. Finally, depletion of TM4SF1 inhibited metastasis and tumour growth in a xenograft mouse model.Conclusions: Our study substantiates a novel mechanism by which TM4SF1 maintains cancer cell stemness and EMT via the Wnt/β-catenin/c-Myc/SOX2 axis during the recurrence and metastasis of CRC.

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Zoledronic acid inhibits the growth of cancer stem cell derived from cervical cancer cell by attenuating their stemness phenotype and inducing apoptosis and cell cycle arrest through the Erk1/2 and Akt pathways

Cited by 48 publications

References 54 publications

Carbon-Ion Beam Irradiation Alone or in Combination with Zoledronic acid Effectively Kills Osteosarcoma Cells

Carbon-Ion Beam Irradiation Alone or in Combination with Zoledronic acid Effectively Kills Osteosarcoma Cells

Aldehyde dehydrogenase 1, a target of miR‑222, is expressed at elevated levels in cervical cancer

TM4SF1 promotes EMT and cancer stemness via the Wnt/β-catenin/SOX2 pathway in colorectal cancer

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