P-glycoprotein associates with Anxa2 and promotes invasion in multidrug resistant breast cancer cells

Zhang, Fei; Zhang, Haichang; Wang, Zhiyong; Yu, Man; Tian, Ran; Ji, Wei; Yang, Yi; Niu, Ruifang

doi:10.1016/j.bcp.2013.11.003

Cited by 64 publications

(68 citation statements)

References 60 publications

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“…The increased expression levels of Anxa2 in cancer tissues are associated with rapid recurrence [21,45], metastasis [32,52], poor response to chemotherapy [6,20], and poor prognosis [32,45]. Importantly, Anxa2 promotes cell adhesion [44], migration [40,44,59,61,62], invasion [51,57,59,61], EMT [63,64], and angiogenesis [26,38], which are crucial for cancer metastasis. In vitro studies demonstrated that Anxa2 downregulation significantly blocks cell cycle progression, cell division, and cell proliferation in cell lines derived from multiple myeloma [2], breast cancer [42,58], and lung cancer [47]; conversely, Anxa2 upregulation promotes cancer cell proliferation [51], these studies presented the implication of Anxa2 in cell cycle progression and cell proliferation.…”

Section: Introductionmentioning

confidence: 97%

RNAi-mediated silencing of Anxa2 inhibits breast cancer cell proliferation by downregulating cyclin D1 in STAT3-dependent pathway

Zhang

Wang

Yuan

et al. 2015

Breast Cancer Res Treat

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Although the upregulated expression of Anxa2 has been implicated in carcinogenesis, cancer progression, and poor prognosis of cancer patients, the detailed molecular mechanisms involved in these processes remain unclear. In this study, we investigated the effect of Anxa2 downregulation with small interference RNA on breast cancer proliferation. To explore molecular mechanisms underlying Anxa2-mediated cancer cell proliferation. We analyzed cell cycle distribution and signaling pathways using semi-quantitative real-time PCR and Western blotting. Anxa2 depletion in breast cancer cells significantly inhibited cell proliferation by decelerating cell cycle progression. The retarded G1-to-S phase transition in Anxa2-silenced cells was attributed to the decreased levels of cyclin D1, which is a crucial promoting factor for cell proliferation because it regulates G1-to-S phase transition during cell cycle progression. We provided evidence that Anxa2 regulates epidermal growth factor-induced phosphorylation of STAT3. The reduced expression of phosphorylated STAT3 is the main factor responsible for decreased cyclin D1 levels in Anxa2-silenced breast cancer cells. Our results revealed the direct relationship between Anxa2 and activation of STAT3, a key transcription factor that plays a pivotal role in regulating breast cancer proliferation and survival. This study provides novel insights into the functions of Anxa2 as a critical molecule in cellular signal transduction and significantly improves our understanding of the mechanism through which Anxa2 regulates cell cycle and cancer cell proliferation.

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Section: Introductionmentioning

confidence: 97%

RNAi-mediated silencing of Anxa2 inhibits breast cancer cell proliferation by downregulating cyclin D1 in STAT3-dependent pathway

Zhang

Wang

Yuan

et al. 2015

Breast Cancer Res Treat

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“…Works by Susa et al have found that the inhibition of P-gp expression can improve the sensitivity of osteosarcoma to drugs [26]. In addition, down regulation of P-gp could impair invasion of multidrug resistance (MDR) breast cancer cell [55]. Due to P-gp and CD44 were determinants of MDR and metastases, there may be a direct connection between the two molecules.…”

Section: Discussionmentioning

confidence: 99%

Targeting CD44 by CRISPR-Cas9 in Multi-Drug Resistant Osteosarcoma Cells

Zheng

Wan

Nur

et al. 2018

Cell Physiol Biochem

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Background/Aims: Drug resistance is the main difficulty for the current treatment for osteosarcoma. Cluster of differentiation 44 (CD44) is a receptor for hyaluronic acid (HA) and HA-binding has been proven to participate in various biological tumor activities, including tumor progression, metastasis and drug resistance. In this study, we aimed to determine the effects of CD44 on migration, invasion, proliferation, and the drug-sensitivity of osteosarcoma. Methods: 96 human osteosarcoma tissues from 56 patients were collected to evaluate the expression of CD44 in osteosarcoma tissue by immunohistochemistry. CRISPR-Cas9 system was used to specifically silence CD44 in drug-resistant cell lines (KHOSR2 and U-2OSR2). The migration and invasion activities of cells was demonstrated by wound healing and transwell invasion assay. The proliferation speed of the cells was detected under 3D cell culture condition. Drug resistance of cells was detected by MTT and drug uptake assay. Results: The immunohistochemistry results demonstrated that a high level of CD44 may predict poor survival and higher potential of metastasis, recurrence and drug resistance in patients with osteosarcoma. After knocking-out of CD44 by the CRISPR-Cas9 system, not only the migration and invasion activities of osteosarcoma cells were significantly inhibited, but the drug sensitivity was also enhanced. Conclusion: CD44 silencing could inhibit the development of osteosarcoma migration, invasion, proliferation and ameliorate drug resistance to current treatment in osteosarcoma. This study applies new strategy to target CD44, which may improve the prognosis of osteosarcoma.

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“…75) It was also reported that P-gp mRNA expression levels were positively correlated with breast cancer lymph node status. 76) These studies indicate that P-gp might also work as a signal transducer.…”

Section: Relationship Between P-gp and Cancer Progression And The Romentioning

confidence: 97%

Advances in Studies of P-Glycoprotein and Its Expression Regulators

Yano

Tomono

Ogihara

2018

Biological & Pharmaceutical Bulletin

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This review deals with recent advances in studies on P-glycoprotein (P-gp) and its expression regulators, focusing especially on our own research. Firstly, we describe findings demonstrating that the distribution of P-gp along the small intestine is heterogeneous, which explains why orally administered P-gp substrate drugs often show bimodal changes of plasma concentration. Secondly, we discuss the post-translational regulation of P-gp localization and function by the scaffold proteins ezrin, radixin and moesin (ERM proteins), together with recent reports indicating that tissue-specific differences in regulation by ERM proteins in normal tissues might be retained in corresponding cancerous tissues. Thirdly, we review evidence that P-gp activity is enhanced in the process of epithelial-to-mesenchymal transition (EMT), which is associated with cancer progression, without any increase in expression of P-gp mRNA. Finally, we describe two examples in which P-gp critically influences the brain distribution of drugs, i.e., oseltamivir, where low levels of P-gp associated with early development allow oseltamivir to enter the brain, potentially resulting in neuropsychiatric side effects in children, and cilnidipine, where impairment of P-gp function in ischemia allows cilnidipine to enter the ischemic brain, where it exerts a neuroprotective action.

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P-glycoprotein associates with Anxa2 and promotes invasion in multidrug resistant breast cancer cells

Cited by 64 publications

References 60 publications

RNAi-mediated silencing of Anxa2 inhibits breast cancer cell proliferation by downregulating cyclin D1 in STAT3-dependent pathway

RNAi-mediated silencing of Anxa2 inhibits breast cancer cell proliferation by downregulating cyclin D1 in STAT3-dependent pathway

Targeting CD44 by CRISPR-Cas9 in Multi-Drug Resistant Osteosarcoma Cells

Advances in Studies of P-Glycoprotein and Its Expression Regulators

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