Restricting extracellular Ca2+ on gefitinib-resistant non-small cell lung cancer cells reverses altered epidermal growth factor-mediated Ca2+ response, which consequently enhances gefitinib sensitivity
Non-small cell lung cancer (NSCLC), one of the leading causes of cancer-related death, has a low 5-year survival rate owing to the inevitable acquired resistance toward antitumor drugs, platinum-based chemotherapy, and targeted therapy. Epidermal growth factor (EGF)-EGF receptor (EGFR) signaling act...
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| description | Non-small cell lung cancer (NSCLC), one of the leading causes of cancer-related death, has a low 5-year survival rate owing to the inevitable acquired resistance toward antitumor drugs, platinum-based chemotherapy, and targeted therapy. Epidermal growth factor (EGF)-EGF receptor (EGFR) signaling activates downstream events leading to phospholipase C/inositol trisphosphate (IP3)/Ca2+ release from IP3-sensitive Ca2+ stores to modulate cell proliferation, motility, and invasion. However, the role of EGFR-mediated Ca2+ signaling in acquired drug resistance is not fully understood. Here, we analyzed alterations of intracellular Ca2+ ([Ca2+]i) responses between gefitinib-sensitive NSCLC PC-9 cells and gefitinib-resistant NSCLC PC-9/GR cells, and we found that acute EGF treatment elicited intracellular Ca2+ ([Ca2+]i) oscillations in PC-9 cells but not in PC-9/GR cells. PC-9/GR cells presented a more sustained basal [Ca2+]i level, lower endoplasmic reticulum Ca2+ level, and higher spontaneous extracellular Ca2+ ([Ca2+]e) influx than PC-9 cells. Notably, restricting [Ca2+]e in both cell types induced identical [Ca2+]i oscillations, dependent on phospholipase C and EGFR activation. Consequently, restricting [Ca2+]e in PC-9/GR cells upregulated gefitinib-mediated poly (ADP-ribose) polymerase cleavage, an increase in Bax/Bcl-2 ratio, cytotoxicity, and apoptosis. In addition, nuclear factor of activated T cell (NFAT1) induction in response to EGF was inhibited by gefitinib in PC-9 cells, whereas EGF-mediated NFAT1 induction in PC-9/GR cells was sustained regardless of gefitinib treatment. Restricting [Ca2+]e in PC-9/GR cells significantly reduced EGF-mediated NFAT1 induction. These findings indicate that spontaneous [Ca2+]e influx in NSCLC cells plays a pivotal role in developing acquired drug resistance and suggest that restricting [Ca2+]e may be a potential strategy for modulating drug-sensitivity. |
| doi_str_mv | 10.1371/journal.pone.0238155 |
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Epidermal growth factor (EGF)-EGF receptor (EGFR) signaling activates downstream events leading to phospholipase C/inositol trisphosphate (IP3)/Ca2+ release from IP3-sensitive Ca2+ stores to modulate cell proliferation, motility, and invasion. However, the role of EGFR-mediated Ca2+ signaling in acquired drug resistance is not fully understood. Here, we analyzed alterations of intracellular Ca2+ ([Ca2+]i) responses between gefitinib-sensitive NSCLC PC-9 cells and gefitinib-resistant NSCLC PC-9/GR cells, and we found that acute EGF treatment elicited intracellular Ca2+ ([Ca2+]i) oscillations in PC-9 cells but not in PC-9/GR cells. PC-9/GR cells presented a more sustained basal [Ca2+]i level, lower endoplasmic reticulum Ca2+ level, and higher spontaneous extracellular Ca2+ ([Ca2+]e) influx than PC-9 cells. Notably, restricting [Ca2+]e in both cell types induced identical [Ca2+]i oscillations, dependent on phospholipase C and EGFR activation. Consequently, restricting [Ca2+]e in PC-9/GR cells upregulated gefitinib-mediated poly (ADP-ribose) polymerase cleavage, an increase in Bax/Bcl-2 ratio, cytotoxicity, and apoptosis. In addition, nuclear factor of activated T cell (NFAT1) induction in response to EGF was inhibited by gefitinib in PC-9 cells, whereas EGF-mediated NFAT1 induction in PC-9/GR cells was sustained regardless of gefitinib treatment. Restricting [Ca2+]e in PC-9/GR cells significantly reduced EGF-mediated NFAT1 induction. These findings indicate that spontaneous [Ca2+]e influx in NSCLC cells plays a pivotal role in developing acquired drug resistance and suggest that restricting [Ca2+]e may be a potential strategy for modulating drug-sensitivity.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0238155</identifier><identifier>PMID: 32841278</identifier><language>eng</language><publisher>San Francisco: Public Library of Science</publisher><subject>Adenosine diphosphate ; Apoptosis ; Bcl-2 protein ; Biology and Life Sciences ; Calcium (extracellular) ; Calcium (intracellular) ; Calcium (reticular) ; Calcium influx ; Calcium ions ; Calcium signalling ; Cell proliferation ; Chemotherapy ; Cytotoxicity ; Drug resistance ; Endoplasmic reticulum ; Epidermal growth factor ; Epidermal growth factor receptors ; Gefitinib ; Growth factors ; Inhibitor drugs ; Inositol trisphosphate ; Intracellular ; Kinases ; Lung cancer ; Lung diseases ; Lymphocytes ; Medicine and Health Sciences ; Mutation ; NF-AT1 protein ; Non-small cell lung carcinoma ; Oscillations ; Phospholipase ; Phospholipase C ; Platinum ; Ribose ; Sensitivity enhancement ; Signaling ; Survival ; Targeted cancer therapy ; Toxicity</subject><ispartof>PloS one, 2020-08, Vol.15 (8), p.e0238155-e0238155</ispartof><rights>2020 Kim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2020 Kim et al 2020 Kim et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c433t-af525535680a9f236ed0ddb52fbba26aa86652d4d9c8ec9de20b8dd0589888013</citedby><cites>FETCH-LOGICAL-c433t-af525535680a9f236ed0ddb52fbba26aa86652d4d9c8ec9de20b8dd0589888013</cites><orcidid>0000-0003-0071-0830</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447054/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447054/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,725,778,782,862,883,2098,2917,23853,27911,27912,53778,53780,79355,79356</link.rule.ids></links><search><contributor>Lee, Jung Weon</contributor><creatorcontrib>Kim, Mi Seong</creatorcontrib><creatorcontrib>Kim, So Hui</creatorcontrib><creatorcontrib>Yang, Sei Hoon</creatorcontrib><creatorcontrib>Kim, Min Seuk</creatorcontrib><title>Restricting extracellular Ca2+ on gefitinib-resistant non-small cell lung cancer cells reverses altered epidermal growth factor-mediated Ca2+ response, which consequently enhances gefitinib sensitivity</title><title>PloS one</title><description>Non-small cell lung cancer (NSCLC), one of the leading causes of cancer-related death, has a low 5-year survival rate owing to the inevitable acquired resistance toward antitumor drugs, platinum-based chemotherapy, and targeted therapy. Epidermal growth factor (EGF)-EGF receptor (EGFR) signaling activates downstream events leading to phospholipase C/inositol trisphosphate (IP3)/Ca2+ release from IP3-sensitive Ca2+ stores to modulate cell proliferation, motility, and invasion. However, the role of EGFR-mediated Ca2+ signaling in acquired drug resistance is not fully understood. Here, we analyzed alterations of intracellular Ca2+ ([Ca2+]i) responses between gefitinib-sensitive NSCLC PC-9 cells and gefitinib-resistant NSCLC PC-9/GR cells, and we found that acute EGF treatment elicited intracellular Ca2+ ([Ca2+]i) oscillations in PC-9 cells but not in PC-9/GR cells. PC-9/GR cells presented a more sustained basal [Ca2+]i level, lower endoplasmic reticulum Ca2+ level, and higher spontaneous extracellular Ca2+ ([Ca2+]e) influx than PC-9 cells. Notably, restricting [Ca2+]e in both cell types induced identical [Ca2+]i oscillations, dependent on phospholipase C and EGFR activation. Consequently, restricting [Ca2+]e in PC-9/GR cells upregulated gefitinib-mediated poly (ADP-ribose) polymerase cleavage, an increase in Bax/Bcl-2 ratio, cytotoxicity, and apoptosis. In addition, nuclear factor of activated T cell (NFAT1) induction in response to EGF was inhibited by gefitinib in PC-9 cells, whereas EGF-mediated NFAT1 induction in PC-9/GR cells was sustained regardless of gefitinib treatment. Restricting [Ca2+]e in PC-9/GR cells significantly reduced EGF-mediated NFAT1 induction. These findings indicate that spontaneous [Ca2+]e influx in NSCLC cells plays a pivotal role in developing acquired drug resistance and suggest that restricting [Ca2+]e may be a potential strategy for modulating drug-sensitivity.</description><subject>Adenosine diphosphate</subject><subject>Apoptosis</subject><subject>Bcl-2 protein</subject><subject>Biology and Life Sciences</subject><subject>Calcium (extracellular)</subject><subject>Calcium (intracellular)</subject><subject>Calcium (reticular)</subject><subject>Calcium influx</subject><subject>Calcium ions</subject><subject>Calcium signalling</subject><subject>Cell proliferation</subject><subject>Chemotherapy</subject><subject>Cytotoxicity</subject><subject>Drug resistance</subject><subject>Endoplasmic reticulum</subject><subject>Epidermal growth factor</subject><subject>Epidermal growth factor receptors</subject><subject>Gefitinib</subject><subject>Growth factors</subject><subject>Inhibitor drugs</subject><subject>Inositol trisphosphate</subject><subject>Intracellular</subject><subject>Kinases</subject><subject>Lung cancer</subject><subject>Lung diseases</subject><subject>Lymphocytes</subject><subject>Medicine and Health Sciences</subject><subject>Mutation</subject><subject>NF-AT1 protein</subject><subject>Non-small cell lung carcinoma</subject><subject>Oscillations</subject><subject>Phospholipase</subject><subject>Phospholipase C</subject><subject>Platinum</subject><subject>Ribose</subject><subject>Sensitivity enhancement</subject><subject>Signaling</subject><subject>Survival</subject><subject>Targeted cancer 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extracellular Ca2+ on gefitinib-resistant non-small cell lung cancer cells reverses altered epidermal growth factor-mediated Ca2+ response, which consequently enhances gefitinib sensitivity</title><author>Kim, Mi Seong ; Kim, So Hui ; Yang, Sei Hoon ; Kim, Min Seuk</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c433t-af525535680a9f236ed0ddb52fbba26aa86652d4d9c8ec9de20b8dd0589888013</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Adenosine diphosphate</topic><topic>Apoptosis</topic><topic>Bcl-2 protein</topic><topic>Biology and Life Sciences</topic><topic>Calcium (extracellular)</topic><topic>Calcium (intracellular)</topic><topic>Calcium (reticular)</topic><topic>Calcium influx</topic><topic>Calcium ions</topic><topic>Calcium signalling</topic><topic>Cell proliferation</topic><topic>Chemotherapy</topic><topic>Cytotoxicity</topic><topic>Drug 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one</jtitle><date>2020-08-25</date><risdate>2020</risdate><volume>15</volume><issue>8</issue><spage>e0238155</spage><epage>e0238155</epage><pages>e0238155-e0238155</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Non-small cell lung cancer (NSCLC), one of the leading causes of cancer-related death, has a low 5-year survival rate owing to the inevitable acquired resistance toward antitumor drugs, platinum-based chemotherapy, and targeted therapy. Epidermal growth factor (EGF)-EGF receptor (EGFR) signaling activates downstream events leading to phospholipase C/inositol trisphosphate (IP3)/Ca2+ release from IP3-sensitive Ca2+ stores to modulate cell proliferation, motility, and invasion. However, the role of EGFR-mediated Ca2+ signaling in acquired drug resistance is not fully understood. Here, we analyzed alterations of intracellular Ca2+ ([Ca2+]i) responses between gefitinib-sensitive NSCLC PC-9 cells and gefitinib-resistant NSCLC PC-9/GR cells, and we found that acute EGF treatment elicited intracellular Ca2+ ([Ca2+]i) oscillations in PC-9 cells but not in PC-9/GR cells. PC-9/GR cells presented a more sustained basal [Ca2+]i level, lower endoplasmic reticulum Ca2+ level, and higher spontaneous extracellular Ca2+ ([Ca2+]e) influx than PC-9 cells. Notably, restricting [Ca2+]e in both cell types induced identical [Ca2+]i oscillations, dependent on phospholipase C and EGFR activation. Consequently, restricting [Ca2+]e in PC-9/GR cells upregulated gefitinib-mediated poly (ADP-ribose) polymerase cleavage, an increase in Bax/Bcl-2 ratio, cytotoxicity, and apoptosis. In addition, nuclear factor of activated T cell (NFAT1) induction in response to EGF was inhibited by gefitinib in PC-9 cells, whereas EGF-mediated NFAT1 induction in PC-9/GR cells was sustained regardless of gefitinib treatment. Restricting [Ca2+]e in PC-9/GR cells significantly reduced EGF-mediated NFAT1 induction. These findings indicate that spontaneous [Ca2+]e influx in NSCLC cells plays a pivotal role in developing acquired drug resistance and suggest that restricting [Ca2+]e may be a potential strategy for modulating drug-sensitivity.</abstract><cop>San Francisco</cop><pub>Public Library of Science</pub><pmid>32841278</pmid><doi>10.1371/journal.pone.0238155</doi><orcidid>https://orcid.org/0000-0003-0071-0830</orcidid><oa>free_for_read</oa></addata></record> |
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| issn | 1932-6203 1932-6203 |
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| subjects | Adenosine diphosphate Apoptosis Bcl-2 protein Biology and Life Sciences Calcium (extracellular) Calcium (intracellular) Calcium (reticular) Calcium influx Calcium ions Calcium signalling Cell proliferation Chemotherapy Cytotoxicity Drug resistance Endoplasmic reticulum Epidermal growth factor Epidermal growth factor receptors Gefitinib Growth factors Inhibitor drugs Inositol trisphosphate Intracellular Kinases Lung cancer Lung diseases Lymphocytes Medicine and Health Sciences Mutation NF-AT1 protein Non-small cell lung carcinoma Oscillations Phospholipase Phospholipase C Platinum Ribose Sensitivity enhancement Signaling Survival Targeted cancer therapy Toxicity |
| title | Restricting extracellular Ca2+ on gefitinib-resistant non-small cell lung cancer cells reverses altered epidermal growth factor-mediated Ca2+ response, which consequently enhances gefitinib sensitivity |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-15T18%3A00%3A23IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Restricting%20extracellular%20Ca2+%20on%20gefitinib-resistant%20non-small%20cell%20lung%20cancer%20cells%20reverses%20altered%20epidermal%20growth%20factor-mediated%20Ca2+%C2%A0response,%20which%20consequently%20enhances%20gefitinib%20sensitivity&rft.jtitle=PloS%20one&rft.au=Kim,%20Mi%20Seong&rft.date=2020-08-25&rft.volume=15&rft.issue=8&rft.spage=e0238155&rft.epage=e0238155&rft.pages=e0238155-e0238155&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0238155&rft_dat=%3Cproquest_plos_%3E2437404752%3C/proquest_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2437106640&rft_id=info:pmid/32841278&rft_doaj_id=oai_doaj_org_article_f4d4d3bce10e44799754f3f3330ee1bc&rfr_iscdi=true |