FZD1 activates protein kinase C delta-mediated drug-resistance in multidrug-resistant MES-SA/Dx5 cancer cells

Hung, Tsai-Hsien; Chen, Chuan-Mu; Tseng, Ching Ping; Shen, Chi–Yen; Wang, Huiling; Choo, Kong‐Bung; Chong, Kowit-Yu

doi:10.1016/j.biocel.2014.04.011

Cited by 18 publications

(16 citation statements)

References 66 publications

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“…Currently, multi drug resistant 1 ( MDR1 ) is frequently associated with the overexpression of membrane‐embedded drug efflux transporters, such as ATP‐binding cassette transporters, known as P‐glycoprotein 1 (P‐gp) (also named ABCB1 ([TP‐binding Cassette Sub‐family B Member 1]), leading to the reduced accumulation of chemotherapeutic drugs and chemoresistance in LMS cells . Hung et al reported that the overexpression of frizzled 1 (FZD1) encoded by FZD1 gene, which is a G‐protein‐coupled receptor and involved in the Wnt/β‐catenin pathway, was observed in LMS cells and contributed to doxorubicin‐resistance via the activation of the protein kinase C δ/AP‐1 signaling transduction pathway, resulting in enhanced ABCB1 expression . Lin et al reported on the important role of progesterone receptor membrane component 1 (PGRMC1) encoded by PGRMC1 , which is an adapter protein mediating cholesterol synthesis, steroid signaling and cytochrome p450 activation.…”

Section: Uterine Leiomyosarcomamentioning

confidence: 99%

“…13 Hung et al reported that the overexpression of frizzled 1 (FZD1) encoded by FZD1 gene, which is a G-protein-coupled receptor and involved in the Wnt/bcatenin pathway, was observed in LMS cells and contributed to doxorubicin-resistance via the activation of the protein kinase C d/AP-1 signaling transduction pathway, resulting in enhanced ABCB1 expression. 14 15 In the last decade, several anticancer drugs or multityrosine kinase inhibitors have demonstrated efficacy with respect to progression-free survival and overall survival, particularly the tyrosine kinase inhibitor (TKI) pazopanib in the treatment of u-LMS. 16 However, the biological mechanisms or optimal predictive biomarkers for these therapies are still being explored.…”

Section: Whole Molecular Mechanisms Of Tumor Development Metastasimentioning

confidence: 99%

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Molecular biomarkers for uterine leiomyosarcoma and endometrial stromal sarcoma

Tsuyoshi

Yoshida

2018

Cancer Science

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Uterine leiomyosarcoma (u‐LMS) and endometrial stromal sarcoma (ESS) are among the most frequent soft tissue sarcomas, which, in adults, lead to fatal lung metastases and patients have an extremely poor prognosis. Due to their rarity and heterogeneity, there are no suitable biomarkers for diagnosis and prognosis, although some biomarker candidates have appeared. In 2017, The Cancer Genome Atlas (TCGA) Research Network's work on u‐LMS has confirmed mutations and deletions in RB1,TP53 and PTEN. In addition, whole‐exome sequencing of u‐LMS has confirmed and demonstrated frequent alterations in TP53,RB1, α‐thalassemia/mental retardation syndrome X‐linked (ATRX) and mediator complex subunit 12 (MED12). MED12 is a useful biomarker to diagnose uterine‐derived LMS and tumors arising from (LM) with a relatively favorable prognosis. TP53 and ATRX mutations can be important mechanisms in the pathogenesis of u‐LMS and are correlated with a poor prognosis. In an update based on the 2014 WHO classification, low‐grade ESS is often associated with gene rearrangement bringing about the JAZF 1‐SUZ12 (formerly JAZF1‐JJAZ1) fusion gene, whereas high‐grade ESS is associated with the YWHAE‐NUTM fusion gene. Low‐grade ESS with JAZF1 rearrangement may correlate with metastasis. However, high‐grade ESS with metastasis with YWHAE rearrangement shows a relatively favorable prognosis. The genetic/molecular genetic aberrations in u‐LMS and ESS are reviewed, focusing on molecular biomarkers for these primary and metastatic tumors.

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Section: Uterine Leiomyosarcomamentioning

confidence: 99%

Section: Whole Molecular Mechanisms Of Tumor Development Metastasimentioning

confidence: 99%

Molecular biomarkers for uterine leiomyosarcoma and endometrial stromal sarcoma

Tsuyoshi

Yoshida

2018

Cancer Science

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“…Western blot was performed as described previously. 35 Briefly, approximately 40 mg of total proteins was loaded onto each lane and the proteins were separated in SDS-PAGE gels. After electrophoresis, the resolved proteins were transferred to PVDF membrane (EMD Millipore, IPVH00010) and subsequently stained with Ponceau S (Sigma-Aldrich, P7170) to confirm complete protein transfer.…”

Section: Western Blot Analysismentioning

confidence: 99%

Wnt pathway activation and ABCB1 expression account for attenuation of Proteasome inhibitor-mediated apoptosis in multidrug-resistant cancer cells

Chong

Hsu

Hung

et al. 2015

Cancer Biology & Therapy

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Multiple drug resistance (MDR) is a major obstacle to attenuating the effectiveness of chemotherapy to many human malignancies. Proteasome inhibition induces apoptosis in a variety of cancer cells and is recognized as a novel anticancer therapy approach. Despite its success, some multiple myeloma patients are resistant or become refractory to ongoing treatment by bortezomib suggesting that chemoresistant cancer cells may have developed a novel mechanism directed against the proteasome inhibitor. The present study aimed to investigate potential mechanism(s) of attenuation in a MDR cell line, MES-SA/Dx5. We found that compared to the parental human uterus sarcoma cell line MES-SA cells, MES-SA/Dx5 cells highly expressed the ABCB1 was more resistant to MG132 and bortezomib, escaping the proteasome inhibitor-induced apoptosis pathway. The resistance was reversed by co-treatment of MG132 and the ABCB1 inhibitor verapamil. The data indicated that ABCB1 might play a role in the efflux of MG132 from the MES-SA/Dx5 cells to reduce MG132-induced apoptosis. Furthermore, the canonical Wnt pathway was found activated only in the MES-SA/Dx5 cells through active β-catenin and related transactivation activities. Western blot analysis demonstrated that Wnt-targeting genes, including c-Myc and cyclin D1, were upregulated and were relevant in inhibiting the expression of p21 in MES-SA/Dx5 cells. On the other hand, MES-SA cells expressed high levels of p21 and downregulated cyclin D1 and caused cell cycle arrest. Together, our study demonstrated the existence and participation of ABCB1 and the Wnt pathway in an MDR cell line that attenuated proteasome inhibitor-induced apoptosis.

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“…Briefly, cells were plated at a density of 1×10 5 in a 24-well plate, lysed with Passive Lysis Buffer, and assayed by the DualLuciferase Reporter Assay System (Hung et al 2014a). The luminescence intensity was measured by a GLOMAX 20/20 Luminometer.…”

Section: Luciferase Activity Assaymentioning

confidence: 99%

Mesenchymal stem cell-based HSP70 promoter-driven VEGFA induction by resveratrol promotes angiogenesis in a mouse model

Chen

Lan

Hung

et al. 2015

Cell Stress and Chaperones

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Several studies of stem cell-based gene therapy have indicated that long-lasting regeneration following vessel ischemia may be stimulated through VEGFA gene therapy and/or MSC transplantation for reduction of ischemic injury in limb ischemia and heart failure. The therapeutic potential of MSC transplantation can be further improved by genetically modifying MSCs with genes which enhance angiogenesis following ischemic injury. In the present study, we aimed to develop an approach in MSC-based therapy for repair and mitigation of ischemic injury and regeneration of damaged tissues in ischemic disease. HSP70 promoter-driven VEGFA expression was induced by resveratrol (RSV) in MSCs, and in combination with known RSV biological functions, the protective effects of our approach were investigated by using ex vivo aortic ring coculture system and a 3D scaffolds in vivo model. Results of this investigation demonstrated that HSP promoter-driven VEGFA expression in MSC increased approximately 2-fold over the background VEGFA levels upon HSP70 promoter induction by RSV. Exposure of HUVEC cells to medium containing MSC in which VEGFA had been induced by cis-RSV enhanced tube formation in the treated HUVEC cells. RSV-treated MSC cells differentiated into endothelial-like phenotypes, exhibiting markedly elevated expression of endothelial cell markers. These MSCs also induced aortic ring sprouting, characteristic of neovascular formation from pre-existing vessels, and additionally promoted neovascularization at the MSC transplantation site in a mouse model. These observations support a hypothesis that VEGFA expression induced by cis-RSV acting on the HSP70 promoter in transplanted MSC augments the angiogenic effects of stem cell gene therapy. The use of an inducible system also vastly reduces possible clinical risks associated with constitutive VEGFA expression.

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FZD1 activates protein kinase C delta-mediated drug-resistance in multidrug-resistant MES-SA/Dx5 cancer cells

Cited by 18 publications

References 66 publications

Molecular biomarkers for uterine leiomyosarcoma and endometrial stromal sarcoma

Molecular biomarkers for uterine leiomyosarcoma and endometrial stromal sarcoma

Wnt pathway activation and ABCB1 expression account for attenuation of Proteasome inhibitor-mediated apoptosis in multidrug-resistant cancer cells

Mesenchymal stem cell-based HSP70 promoter-driven VEGFA induction by resveratrol promotes angiogenesis in a mouse model

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