Calcipotriol abrogates cancer-associated fibroblast-derived IL-8-mediated oxaliplatin resistance in gastric cancer cells via blocking PI3K/Akt signaling
Activation of vitamin D receptor (VDR) in cancer-associated fibroblasts (CAFs) has been implicated in hesitating tumor progression and chemoresistance of several human malignancies. Yet, the role of VDR in CAF-induced chemotherapy resistance of gastric cancer (GC) cells remains elusive. In this stud...
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| Veröffentlicht in: | Acta pharmacologica Sinica 2023-01, Vol.44 (1), p.178-188 |
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| creator | Zhao, Zhen-xiong Zhang, Yan-qiu Sun, Hui Chen, Zi-qi Chang, Jin-jia Wang, Xin Wang, Xu Tan, Cong Ni, Shu-juan Weng, Wei-wei Zhang, Meng Wang, Lei Huang, Dan Feng, Yun Sheng, Wei-qi Xu, Mi-die |
| description | Activation of vitamin D receptor (VDR) in cancer-associated fibroblasts (CAFs) has been implicated in hesitating tumor progression and chemoresistance of several human malignancies. Yet, the role of VDR in CAF-induced chemotherapy resistance of gastric cancer (GC) cells remains elusive. In this study we first conducted immunohistochemistry analysis on tissue microarrays including 88 pairs of GC and normal mucosa samples, and provided clinical evidence that VDR was mainly expressed in gastric mucous cells but almost invisible in CAFs, and VDR expression was negatively correlated with malignant clinical phenotype and advanced stages, low VDR expression confers to poor overall survival rate of patients with GC. In a co-culture system of primary CAFs and cancer cells, we showed that treatment of HGC-27 and AGS GC cells with VDR ligand calcipotriol (Cal, 500 nM) significantly inhibited CAF-induced oxaliplatin resistance. By using RNA-sequencing and Human Cytokine Antibody Array, we demonstrated that IL-8 secretion from CAFs induced oxaliplatin resistance via activating the PI3K/AKT pathway in GC, whereas Cal treatment greatly attenuated the tumor-supportive effect of CAF-derived IL-8 on GC cells. Taken together, this study verifies the specific localization of VDR in GC tissues and demonstrates that activation of VDR abrogates CAF-derived IL-8-mediated oxaliplatin resistance in GC via blocking PI3K/Akt signaling, suggesting vitamin D supplementation as a potential strategy of enhancing the anti-tumor effect of chemotherapy in GC. |
| doi_str_mv | 10.1038/s41401-022-00927-1 |
| format | Article |
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Yet, the role of VDR in CAF-induced chemotherapy resistance of gastric cancer (GC) cells remains elusive. In this study we first conducted immunohistochemistry analysis on tissue microarrays including 88 pairs of GC and normal mucosa samples, and provided clinical evidence that VDR was mainly expressed in gastric mucous cells but almost invisible in CAFs, and VDR expression was negatively correlated with malignant clinical phenotype and advanced stages, low VDR expression confers to poor overall survival rate of patients with GC. In a co-culture system of primary CAFs and cancer cells, we showed that treatment of HGC-27 and AGS GC cells with VDR ligand calcipotriol (Cal, 500 nM) significantly inhibited CAF-induced oxaliplatin resistance. By using RNA-sequencing and Human Cytokine Antibody Array, we demonstrated that IL-8 secretion from CAFs induced oxaliplatin resistance via activating the PI3K/AKT pathway in GC, whereas Cal treatment greatly attenuated the tumor-supportive effect of CAF-derived IL-8 on GC cells. Taken together, this study verifies the specific localization of VDR in GC tissues and demonstrates that activation of VDR abrogates CAF-derived IL-8-mediated oxaliplatin resistance in GC via blocking PI3K/Akt signaling, suggesting vitamin D supplementation as a potential strategy of enhancing the anti-tumor effect of chemotherapy in GC.</description><identifier>ISSN: 1671-4083</identifier><identifier>EISSN: 1745-7254</identifier><identifier>DOI: 10.1038/s41401-022-00927-1</identifier><identifier>PMID: 35676532</identifier><language>eng</language><publisher>Singapore: Springer Nature Singapore</publisher><subject>1-Phosphatidylinositol 3-kinase ; AKT protein ; Biomedical and Life Sciences ; Biomedicine ; Cancer-Associated Fibroblasts - metabolism ; Cancer-Associated Fibroblasts - pathology ; Cell culture ; Cell Line, Tumor ; Chemoresistance ; Chemotherapy ; Dietary supplements ; Fibroblasts ; Gastric cancer ; Humans ; Immunohistochemistry ; Immunology ; Interleukin 8 ; Interleukin-8 - metabolism ; Interleukin-8 - pharmacology ; Interleukin-8 - therapeutic use ; Internal Medicine ; Localization ; Malignancy ; Medical Microbiology ; Oxaliplatin ; Oxaliplatin - metabolism ; Oxaliplatin - pharmacology ; Oxaliplatin - therapeutic use ; Pharmacology/Toxicology ; Phenotypes ; Phosphatidylinositol 3-Kinases - metabolism ; Proto-Oncogene Proteins c-akt - metabolism ; Stomach Neoplasms - drug therapy ; Stomach Neoplasms - metabolism ; Tumors ; Vaccine ; Vitamin D receptors</subject><ispartof>Acta pharmacologica Sinica, 2023-01, Vol.44 (1), p.178-188</ispartof><rights>The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society 2022</rights><rights>2022. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.</rights><rights>The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society 2022.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c430t-d6a1aeb946e868112cc116c79eea0f7a58fa9dc4cb25f26d37cddba921a079c93</citedby><cites>FETCH-LOGICAL-c430t-d6a1aeb946e868112cc116c79eea0f7a58fa9dc4cb25f26d37cddba921a079c93</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9813133/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9813133/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35676532$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhao, Zhen-xiong</creatorcontrib><creatorcontrib>Zhang, Yan-qiu</creatorcontrib><creatorcontrib>Sun, Hui</creatorcontrib><creatorcontrib>Chen, Zi-qi</creatorcontrib><creatorcontrib>Chang, Jin-jia</creatorcontrib><creatorcontrib>Wang, Xin</creatorcontrib><creatorcontrib>Wang, Xu</creatorcontrib><creatorcontrib>Tan, Cong</creatorcontrib><creatorcontrib>Ni, Shu-juan</creatorcontrib><creatorcontrib>Weng, Wei-wei</creatorcontrib><creatorcontrib>Zhang, Meng</creatorcontrib><creatorcontrib>Wang, Lei</creatorcontrib><creatorcontrib>Huang, Dan</creatorcontrib><creatorcontrib>Feng, Yun</creatorcontrib><creatorcontrib>Sheng, Wei-qi</creatorcontrib><creatorcontrib>Xu, Mi-die</creatorcontrib><title>Calcipotriol abrogates cancer-associated fibroblast-derived IL-8-mediated oxaliplatin resistance in gastric cancer cells via blocking PI3K/Akt signaling</title><title>Acta pharmacologica Sinica</title><addtitle>Acta Pharmacol Sin</addtitle><addtitle>Acta Pharmacol Sin</addtitle><description>Activation of vitamin D receptor (VDR) in cancer-associated fibroblasts (CAFs) has been implicated in hesitating tumor progression and chemoresistance of several human malignancies. Yet, the role of VDR in CAF-induced chemotherapy resistance of gastric cancer (GC) cells remains elusive. In this study we first conducted immunohistochemistry analysis on tissue microarrays including 88 pairs of GC and normal mucosa samples, and provided clinical evidence that VDR was mainly expressed in gastric mucous cells but almost invisible in CAFs, and VDR expression was negatively correlated with malignant clinical phenotype and advanced stages, low VDR expression confers to poor overall survival rate of patients with GC. In a co-culture system of primary CAFs and cancer cells, we showed that treatment of HGC-27 and AGS GC cells with VDR ligand calcipotriol (Cal, 500 nM) significantly inhibited CAF-induced oxaliplatin resistance. By using RNA-sequencing and Human Cytokine Antibody Array, we demonstrated that IL-8 secretion from CAFs induced oxaliplatin resistance via activating the PI3K/AKT pathway in GC, whereas Cal treatment greatly attenuated the tumor-supportive effect of CAF-derived IL-8 on GC cells. Taken together, this study verifies the specific localization of VDR in GC tissues and demonstrates that activation of VDR abrogates CAF-derived IL-8-mediated oxaliplatin resistance in GC via blocking PI3K/Akt signaling, suggesting vitamin D supplementation as a potential strategy of enhancing the anti-tumor effect of chemotherapy in GC.</description><subject>1-Phosphatidylinositol 3-kinase</subject><subject>AKT protein</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Cancer-Associated Fibroblasts - metabolism</subject><subject>Cancer-Associated Fibroblasts - pathology</subject><subject>Cell culture</subject><subject>Cell Line, Tumor</subject><subject>Chemoresistance</subject><subject>Chemotherapy</subject><subject>Dietary supplements</subject><subject>Fibroblasts</subject><subject>Gastric cancer</subject><subject>Humans</subject><subject>Immunohistochemistry</subject><subject>Immunology</subject><subject>Interleukin 8</subject><subject>Interleukin-8 - 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Yet, the role of VDR in CAF-induced chemotherapy resistance of gastric cancer (GC) cells remains elusive. In this study we first conducted immunohistochemistry analysis on tissue microarrays including 88 pairs of GC and normal mucosa samples, and provided clinical evidence that VDR was mainly expressed in gastric mucous cells but almost invisible in CAFs, and VDR expression was negatively correlated with malignant clinical phenotype and advanced stages, low VDR expression confers to poor overall survival rate of patients with GC. In a co-culture system of primary CAFs and cancer cells, we showed that treatment of HGC-27 and AGS GC cells with VDR ligand calcipotriol (Cal, 500 nM) significantly inhibited CAF-induced oxaliplatin resistance. By using RNA-sequencing and Human Cytokine Antibody Array, we demonstrated that IL-8 secretion from CAFs induced oxaliplatin resistance via activating the PI3K/AKT pathway in GC, whereas Cal treatment greatly attenuated the tumor-supportive effect of CAF-derived IL-8 on GC cells. Taken together, this study verifies the specific localization of VDR in GC tissues and demonstrates that activation of VDR abrogates CAF-derived IL-8-mediated oxaliplatin resistance in GC via blocking PI3K/Akt signaling, suggesting vitamin D supplementation as a potential strategy of enhancing the anti-tumor effect of chemotherapy in GC.</abstract><cop>Singapore</cop><pub>Springer Nature Singapore</pub><pmid>35676532</pmid><doi>10.1038/s41401-022-00927-1</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Acta pharmacologica Sinica, 2023-01, Vol.44 (1), p.178-188 |
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| subjects | 1-Phosphatidylinositol 3-kinase AKT protein Biomedical and Life Sciences Biomedicine Cancer-Associated Fibroblasts - metabolism Cancer-Associated Fibroblasts - pathology Cell culture Cell Line, Tumor Chemoresistance Chemotherapy Dietary supplements Fibroblasts Gastric cancer Humans Immunohistochemistry Immunology Interleukin 8 Interleukin-8 - metabolism Interleukin-8 - pharmacology Interleukin-8 - therapeutic use Internal Medicine Localization Malignancy Medical Microbiology Oxaliplatin Oxaliplatin - metabolism Oxaliplatin - pharmacology Oxaliplatin - therapeutic use Pharmacology/Toxicology Phenotypes Phosphatidylinositol 3-Kinases - metabolism Proto-Oncogene Proteins c-akt - metabolism Stomach Neoplasms - drug therapy Stomach Neoplasms - metabolism Tumors Vaccine Vitamin D receptors |
| title | Calcipotriol abrogates cancer-associated fibroblast-derived IL-8-mediated oxaliplatin resistance in gastric cancer cells via blocking PI3K/Akt signaling |
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