Loss of TRPM2 function protects against irradiation-induced salivary gland dysfunction
Xerostomia as a result of salivary gland damage is a permanent and debilitating side effect of radiotherapy for head and neck cancers. Effective treatments for protecting, or restoring, salivary gland function are not available. Here we report that irradiation treatment leads to activation of the ca...
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| Veröffentlicht in: | Nature communications 2013, Vol.4 (1), p.1515-1515, Article 1515 |
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| creator | Liu, Xibao Cotrim, Ana Teos, Leyla Zheng, Changyu Swaim, William Mitchell, James Mori, Yasuo Ambudkar, Indu |
| description | Xerostomia as a result of salivary gland damage is a permanent and debilitating side effect of radiotherapy for head and neck cancers. Effective treatments for protecting, or restoring, salivary gland function are not available. Here we report that irradiation treatment leads to activation of the calcium-permeable channel, transient potential melastatin-like 2 (TRPM2), via stimulation of poly-ADP-ribose polymerase. Importantly, irradiation induced an irreversible loss of salivary gland fluid secretion in TRPM2+/+ mice while a transient loss was seen in TRPM2−/− mice with >60% recovery by 30 days after irradiation. Treatment of TRPM2+/+ mice with the free radical scavenger Tempol or the PARP1 inhibitor 3-aminobenzamide attenuated irradiation-induced activation of TRPM2 and induced significant recovery of salivary fluid secretion. Furthermore, TPL (4-hydroxy-2,2,6,6-tetramethylpiperidine-
N
-oxyl) induced complete recovery of function in irradiated TRPM2−/− mice. These novel data demonstrate that TRPM2 is activated by irradiation, via PARP1 activation, and contributes to irreversible loss of salivary gland function.
A debilitating side effect of radiotherapy in patients with head and neck cancers is xerostomia as a result of salivary gland dysfunction. Here Liu
et al
. show that activation of the calcium channel TRPM2 in salivary gland cells contributes to irradiation-induced loss of salivary fluid secretion. |
| doi_str_mv | 10.1038/ncomms2526 |
| format | Article |
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N
-oxyl) induced complete recovery of function in irradiated TRPM2−/− mice. These novel data demonstrate that TRPM2 is activated by irradiation, via PARP1 activation, and contributes to irreversible loss of salivary gland function.
A debilitating side effect of radiotherapy in patients with head and neck cancers is xerostomia as a result of salivary gland dysfunction. Here Liu
et al
. show that activation of the calcium channel TRPM2 in salivary gland cells contributes to irradiation-induced loss of salivary fluid secretion.</description><identifier>ISSN: 2041-1723</identifier><identifier>EISSN: 2041-1723</identifier><identifier>DOI: 10.1038/ncomms2526</identifier><identifier>PMID: 23443543</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>631/67/1059/485 ; 692/308 ; 692/700/565/2194 ; Acinar Cells - drug effects ; Acinar Cells - metabolism ; Acinar Cells - pathology ; Acinar Cells - radiation effects ; Animals ; Benzamides - pharmacology ; Calcium - metabolism ; Cancer therapies ; Carbachol - pharmacology ; Cell Line ; Cell Survival - drug effects ; Cell Survival - radiation effects ; Enzyme Inhibitors - pharmacology ; Exocrine glands ; Free radicals ; Head & neck cancer ; Humanities and Social Sciences ; Humans ; Hydrogen Peroxide - pharmacology ; Ion Channel Gating - drug effects ; Ion Channel Gating - radiation effects ; Mice ; Mice, Inbred C57BL ; multidisciplinary ; Physiology ; Piperidines - pharmacology ; Poly(ADP-ribose) Polymerase Inhibitors ; Poly(ADP-ribose) Polymerases - metabolism ; Radiation Injuries - pathology ; Radiation Injuries - physiopathology ; Radiation Injuries - prevention & control ; Radiation therapy ; Saliva - drug effects ; Saliva - radiation effects ; Saliva - secretion ; Salivary Glands - metabolism ; Salivary Glands - pathology ; Salivary Glands - physiopathology ; Salivary Glands - radiation effects ; Salivation - drug effects ; Salivation - radiation effects ; Science ; Science (multidisciplinary) ; Submandibular Gland - metabolism ; Submandibular Gland - pathology ; Submandibular Gland - physiopathology ; Submandibular Gland - radiation effects ; TRPM Cation Channels - deficiency ; TRPM Cation Channels - metabolism ; X-Rays</subject><ispartof>Nature communications, 2013, Vol.4 (1), p.1515-1515, Article 1515</ispartof><rights>Springer Nature Limited 2013</rights><rights>Copyright Nature Publishing Group Feb 2013</rights><rights>2013 . 2013</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c508t-7d755f7d9efdc41f415eff63cdb95402fd0111233543690949c9b70c5b0cfb7a3</citedby><cites>FETCH-LOGICAL-c508t-7d755f7d9efdc41f415eff63cdb95402fd0111233543690949c9b70c5b0cfb7a3</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/PMC4059199/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4059199/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,4022,27921,27922,27923,41118,42187,51574,53789,53791</link.rule.ids><linktorsrc>$$Uhttps://doi.org/10.1038/ncomms2526$$EView_record_in_Springer_Nature$$FView_record_in_$$GSpringer_Nature</linktorsrc><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23443543$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Liu, Xibao</creatorcontrib><creatorcontrib>Cotrim, Ana</creatorcontrib><creatorcontrib>Teos, Leyla</creatorcontrib><creatorcontrib>Zheng, Changyu</creatorcontrib><creatorcontrib>Swaim, William</creatorcontrib><creatorcontrib>Mitchell, James</creatorcontrib><creatorcontrib>Mori, Yasuo</creatorcontrib><creatorcontrib>Ambudkar, Indu</creatorcontrib><title>Loss of TRPM2 function protects against irradiation-induced salivary gland dysfunction</title><title>Nature communications</title><addtitle>Nat Commun</addtitle><addtitle>Nat Commun</addtitle><description>Xerostomia as a result of salivary gland damage is a permanent and debilitating side effect of radiotherapy for head and neck cancers. Effective treatments for protecting, or restoring, salivary gland function are not available. Here we report that irradiation treatment leads to activation of the calcium-permeable channel, transient potential melastatin-like 2 (TRPM2), via stimulation of poly-ADP-ribose polymerase. Importantly, irradiation induced an irreversible loss of salivary gland fluid secretion in TRPM2+/+ mice while a transient loss was seen in TRPM2−/− mice with >60% recovery by 30 days after irradiation. Treatment of TRPM2+/+ mice with the free radical scavenger Tempol or the PARP1 inhibitor 3-aminobenzamide attenuated irradiation-induced activation of TRPM2 and induced significant recovery of salivary fluid secretion. Furthermore, TPL (4-hydroxy-2,2,6,6-tetramethylpiperidine-
N
-oxyl) induced complete recovery of function in irradiated TRPM2−/− mice. These novel data demonstrate that TRPM2 is activated by irradiation, via PARP1 activation, and contributes to irreversible loss of salivary gland function.
A debilitating side effect of radiotherapy in patients with head and neck cancers is xerostomia as a result of salivary gland dysfunction. Here Liu
et al
. show that activation of the calcium channel TRPM2 in salivary gland cells contributes to irradiation-induced loss of salivary fluid secretion.</description><subject>631/67/1059/485</subject><subject>692/308</subject><subject>692/700/565/2194</subject><subject>Acinar Cells - drug effects</subject><subject>Acinar Cells - metabolism</subject><subject>Acinar Cells - pathology</subject><subject>Acinar Cells - radiation effects</subject><subject>Animals</subject><subject>Benzamides - pharmacology</subject><subject>Calcium - metabolism</subject><subject>Cancer therapies</subject><subject>Carbachol - pharmacology</subject><subject>Cell Line</subject><subject>Cell Survival - drug effects</subject><subject>Cell Survival - radiation effects</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Exocrine glands</subject><subject>Free radicals</subject><subject>Head & neck cancer</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>Hydrogen Peroxide - pharmacology</subject><subject>Ion Channel Gating - drug effects</subject><subject>Ion Channel Gating - radiation effects</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>multidisciplinary</subject><subject>Physiology</subject><subject>Piperidines - pharmacology</subject><subject>Poly(ADP-ribose) Polymerase Inhibitors</subject><subject>Poly(ADP-ribose) Polymerases - metabolism</subject><subject>Radiation Injuries - pathology</subject><subject>Radiation Injuries - physiopathology</subject><subject>Radiation Injuries - prevention & control</subject><subject>Radiation therapy</subject><subject>Saliva - drug effects</subject><subject>Saliva - radiation effects</subject><subject>Saliva - secretion</subject><subject>Salivary Glands - metabolism</subject><subject>Salivary Glands - pathology</subject><subject>Salivary Glands - physiopathology</subject><subject>Salivary Glands - radiation effects</subject><subject>Salivation - drug 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irradiation-induced salivary gland dysfunction</atitle><jtitle>Nature communications</jtitle><stitle>Nat Commun</stitle><addtitle>Nat Commun</addtitle><date>2013</date><risdate>2013</risdate><volume>4</volume><issue>1</issue><spage>1515</spage><epage>1515</epage><pages>1515-1515</pages><artnum>1515</artnum><issn>2041-1723</issn><eissn>2041-1723</eissn><abstract>Xerostomia as a result of salivary gland damage is a permanent and debilitating side effect of radiotherapy for head and neck cancers. Effective treatments for protecting, or restoring, salivary gland function are not available. Here we report that irradiation treatment leads to activation of the calcium-permeable channel, transient potential melastatin-like 2 (TRPM2), via stimulation of poly-ADP-ribose polymerase. Importantly, irradiation induced an irreversible loss of salivary gland fluid secretion in TRPM2+/+ mice while a transient loss was seen in TRPM2−/− mice with >60% recovery by 30 days after irradiation. Treatment of TRPM2+/+ mice with the free radical scavenger Tempol or the PARP1 inhibitor 3-aminobenzamide attenuated irradiation-induced activation of TRPM2 and induced significant recovery of salivary fluid secretion. Furthermore, TPL (4-hydroxy-2,2,6,6-tetramethylpiperidine-
N
-oxyl) induced complete recovery of function in irradiated TRPM2−/− mice. These novel data demonstrate that TRPM2 is activated by irradiation, via PARP1 activation, and contributes to irreversible loss of salivary gland function.
A debilitating side effect of radiotherapy in patients with head and neck cancers is xerostomia as a result of salivary gland dysfunction. Here Liu
et al
. show that activation of the calcium channel TRPM2 in salivary gland cells contributes to irradiation-induced loss of salivary fluid secretion.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>23443543</pmid><doi>10.1038/ncomms2526</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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| source | Springer Nature OA Free Journals |
| subjects | 631/67/1059/485 692/308 692/700/565/2194 Acinar Cells - drug effects Acinar Cells - metabolism Acinar Cells - pathology Acinar Cells - radiation effects Animals Benzamides - pharmacology Calcium - metabolism Cancer therapies Carbachol - pharmacology Cell Line Cell Survival - drug effects Cell Survival - radiation effects Enzyme Inhibitors - pharmacology Exocrine glands Free radicals Head & neck cancer Humanities and Social Sciences Humans Hydrogen Peroxide - pharmacology Ion Channel Gating - drug effects Ion Channel Gating - radiation effects Mice Mice, Inbred C57BL multidisciplinary Physiology Piperidines - pharmacology Poly(ADP-ribose) Polymerase Inhibitors Poly(ADP-ribose) Polymerases - metabolism Radiation Injuries - pathology Radiation Injuries - physiopathology Radiation Injuries - prevention & control Radiation therapy Saliva - drug effects Saliva - radiation effects Saliva - secretion Salivary Glands - metabolism Salivary Glands - pathology Salivary Glands - physiopathology Salivary Glands - radiation effects Salivation - drug effects Salivation - radiation effects Science Science (multidisciplinary) Submandibular Gland - metabolism Submandibular Gland - pathology Submandibular Gland - physiopathology Submandibular Gland - radiation effects TRPM Cation Channels - deficiency TRPM Cation Channels - metabolism X-Rays |
| title | Loss of TRPM2 function protects against irradiation-induced salivary gland dysfunction |
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