Vitamin D promotes the cisplatin sensitivity of oral squamous cell carcinoma by inhibiting LCN2-modulated NF-κB pathway activation through RPS3

Huang, Zheng‐Ming; Zhang, Yin; Li, Haigang; Zhou, Yufeng; Zhang, Qianyu; Chen, Rui; Jin, Tingting; Hu, Kaishun; Li, Shihao; Wang, Yan; Chen, Wei‐liang; Huang, Zhiquan

doi:10.1038/s41419-019-2177-x

Cited by 66 publications

(74 citation statements)

References 43 publications

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“…In addition, both up-regulation and intrinsic dysfunctions in ribosomes result in an increased incidence of tumors, and RPS3 is involved in radioresistance or invasion of tumor cells [32,33]. Huang et al showed that Vitamin D promotes the cisplatin sensitivity of oral squamous cell carcinoma by inhibiting LCN2modulated NF-κB pathway activation through RPS3 [34]. Zhao et al unveiled a novel extra-ribosomal role of RPS3 in facilitating hepatocarcinogenesis via the post-transcriptional regulation of SIRT1 expression and proposes that the RPS3/SIRT1 pathway serves as a potential therapeutic target in HCC [35].…”

Section: Discussionmentioning

confidence: 99%

Cisplatin-Resistant Gastric Cancer Cells Promote the Chemoresistance of Cisplatin-Sensitive Cells via Exosomal RPS3 Mediated PI3K-Akt-cofilin-1 Signaling Axis

Sun

et al. 2020

Preprint

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Background: Cisplatin is an important agent in first-line chemotherapy against gastric cancer (GC). However, consequential drug resistance limits its effectiveness for the treatment of GC. Exosomes which are loaded with proteins, lipids and RNAs, have been proven to transfer malignant phenotype. This study aims to explore the role and mechanism of exosomal RPS3 protein in transmitting a chemoresistance phenotype from cisplatin resistant to cisplatin sensitive gastric cancer cells.Methods: A cisplatin resistant gastric cancer cell line SGC7901R was established by continuously grafting SGC7901S cells into cisplatin-containing culture medium. Exosomes from SGC7901R and SGC7901S were obtained and confirmed through ultracentrifuge and Nano Analyzer. By LC-MS/MS analysis methods, we detected the differentially expressed proteins in SGC7901R cells exosomes and SGC7901S cells exosomes. Western blotting was used to verify the differential expression of exosomal RPS3 between cisplatin resistant and parental cell lines. Subsequently, a series of in vitro assays and a xenograft tumor model were used to observe the functions of exosomal RPS3 protein in GC.Results: SGC7901R cell derived exosomes were readily taken up by cisplatin sensitive SGC7901S cells, thus triggering off a phenotype of chemoresistance in the receptor cells. Subsequently, it was demonstrated that exosomal RPS3 was essential for inducing chemoresistance of receptor cells as shown by the acquisition of this phenotype in SGC7901S cells with enforced expression of RPS3. Further mechanism study demonstrated that cisplatin‑resistant gastric cancer cells-derived exosomal RPS3 enhanced the chemoresistance of cisplatin‑sensitive gastric cancer cells through the PI3K-Akt-cofilin-1 signaling pathway.Conclusion: Cisplatin resistant gastric cancer cells communicate with sensitive cells through the intercellular delivery of exosomal RPS3 and activation of the PI3K-Akt-cofilin-1 signaling pathway. Targeting exosomal RPS3 protein in cisplatin resistant gastric cancer cells may thus be a promising strategy to overcome cisplatin resistance in gastric cancer.

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Section: Discussionmentioning

confidence: 99%

Cisplatin-Resistant Gastric Cancer Cells Promote the Chemoresistance of Cisplatin-Sensitive Cells via Exosomal RPS3 Mediated PI3K-Akt-cofilin-1 Signaling Axis

Sun

et al. 2020

Preprint

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“…Cancer pharmacological resistance represents the major cause of tumor progression therefore, overcoming drug resistance is now the greatest challenge for scientists. Vitamin D has been reported to reverse resistance mechanisms to chemotherapy [23,24], TKI [28] and other target therapy [25][26][27], as studied in in vitro models of different cancers.…”

Section: Vitamin D and Cancer: Reversal Effects Of Vitamin D On Cancementioning

confidence: 99%

“…Chronic treatment with cisplatin enhanced the protein expression of the oncogene LCN2 by inhibiting methylation at the promoter level. Furthermore, considering that LCN2 overexpression is associated with lymph node metastasis, poor prognosis and post-chemotherapy recurrence, oral cancer cell lines overexpressing LCN2 proteins showed less sensitivity to cisplatin [23]. Surprisingly, vitamin D exposure made oral cancer cells again sensitive to cisplatin by inhibiting LCN2 expression and Nf-kB phosphorylation [23].…”

Section: Vitamin D and Cancer: Reversal Effects Of Vitamin D On Cancementioning

confidence: 99%

“…More recently, accumulating evidence from epidemiological and experimental studies [9,[20][21][22] has demonstrated that vitamin D, when used in combined therapy, increases the effectiveness of anticancer drugs such as gemcitabine [9], cisplatin [9], doxorubicin [21] as well as proton therapy [22] in several cancer models. In addition to synergistic or additive antitumor effectiveness induced by vitamin D supplementation, an emerging role of vitamin D as a reversal agent of drug resistance induced by chemotherapic agents [23,24] as well as target therapy [25][26][27], such as tyrosine kinase inhibitors (TKIs) [28], is spreading. The establishment of multidrug resistance mechanism is increasing in clinical practice, resulting in cancer recurrence and worsening of malignancy.…”

Section: Introductionmentioning

confidence: 99%

“…The establishment of multidrug resistance mechanism is increasing in clinical practice, resulting in cancer recurrence and worsening of malignancy. To date, the molecular mechanisms by which vitamin D may reverse cancer multidrug resistance are still only partially known, and the topic is subject of a few recent studies [23,[25][26][27].…”

Section: Introductionmentioning

confidence: 99%

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Vitamin D-Induced Molecular Mechanisms to Potentiate Cancer Therapy and to Reverse Drug-Resistance in Cancer Cells

et al. 2020

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Increasing interest in studying the role of vitamin D in cancer has been provided by the scientific literature during the last years, although mixed results have been reported. Vitamin D deficiency has been largely associated with various types of solid and non-solid human cancers, and the almost ubiquitous expression of vitamin D receptor (VDR) has always led to suppose a crucial role of vitamin D in cancer. However, the association between vitamin D levels and the risk of solid cancers, such as colorectal, prostate and breast cancer, shows several conflicting results that raise questions about the use of vitamin D supplements in cancer patients. Moreover, studies on vitamin D supplementation do not always show improvements in tumor progression and mortality risk, particularly for prostate and breast cancer. Conversely, several molecular studies are in agreement about the role of vitamin D in inhibiting tumor cell proliferation, growth and invasiveness, cell cycle arrest and inflammatory signaling, through which vitamin D may also regulate cancer microenvironment through the activation of different molecular pathways. More recently, a role in the regulation of cancer stem cells proliferation and short non-coding microRNA (miRNAs) expression has emerged, conferring to vitamin D a more crucial role in cancer development and progression. Interestingly, it has been shown that vitamin D is able not only to potentiate the effects of traditional cancer therapy but can even contribute to overcome the molecular mechanisms of drug resistance—often triggering tumor-spreading. At this regard, vitamin D can act at various levels through the regulation of growth of cancer stem cells and the epithelial–mesenchymal transition (EMT), as well as through the modulation of miRNA gene expression. The current review reconsiders epidemiological and molecular literature concerning the role of vitamin D in cancer risk and tumor development and progression, as well as the action of vitamin D supplementation in potentiating the effects of drug therapy and overcoming the mechanisms of resistance often triggered during cancer therapies, by critically addressing strengths and weaknesses of available data from 2010 to 2020.

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HPV Enhances HNSCC Chemosensitization by Inhibiting SERPINB3 Expression to Disrupt the Fanconi Anemia Pathway

Huang

Chen

et al. 2022

Advanced Science

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Head and neck squamous cell carcinoma (HNSCC) is the most common malignant tumor of the head and neck, and the prognosis of patients is poor due to chemotherapeutic resistance. Interestingly, patients with HNSCC induced by human papillomavirus (HPV) infection are more sensitive to chemotherapy and display a better prognosis than HPV-negative patients. The biological relevance of HPV infection and the mechanism underlying chemosensitivity to cisplatin remain unknown. Herein, SERPINB3 is identified as an important target for regulation of cisplatin sensitivity by HPV-E6/E7 in HNSCC. Downregulation of SERPINB3 inhibits cisplatin-induced DNA damage repair and enhances the cytotoxicity of cisplatin. In detail, decreasing SERPINB3 expression reduces the USP1-mediated deubiquitination of FANCD2-FANCI in the Fanconi anemia pathway, thereby interfering with cisplatin-induced DNA interstrand crosslinks repair and further contributing to HNSCC cell apoptosis. To translate this finding, pH-responsive nanoparticles are used to deliver SERPINB3 small interfering RNA in combination with cisplatin, and this treatment successfully reverses cisplatin chemotherapeutic resistance in a patient-derived xenograft model from HPV-negative HNSCC. Taken together, these findings suggest that targeting SERPINB3 based on HPV-positive HNSCC is a potential strategy to overcome cisplatin resistance in HPV-negative HNSCC and improves the prognosis of this disease.

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Vitamin D promotes the cisplatin sensitivity of oral squamous cell carcinoma by inhibiting LCN2-modulated NF-κB pathway activation through RPS3

Cited by 66 publications

References 43 publications

Cisplatin-Resistant Gastric Cancer Cells Promote the Chemoresistance of Cisplatin-Sensitive Cells via Exosomal RPS3 Mediated PI3K-Akt-cofilin-1 Signaling Axis

Cisplatin-Resistant Gastric Cancer Cells Promote the Chemoresistance of Cisplatin-Sensitive Cells via Exosomal RPS3 Mediated PI3K-Akt-cofilin-1 Signaling Axis

Vitamin D-Induced Molecular Mechanisms to Potentiate Cancer Therapy and to Reverse Drug-Resistance in Cancer Cells

HPV Enhances HNSCC Chemosensitization by Inhibiting SERPINB3 Expression to Disrupt the Fanconi Anemia Pathway

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