Reciprocal regulation of autophagy and dNTP pools in human cancer cells
Ribonucleotide reductase (RNR) plays a critical role in catalyzing the biosynthesis and maintaining the intracellular concentration of 4 deoxyribonucleoside triphosphates (dNTPs). Unbalanced or deficient dNTP pools cause serious genotoxic consequences. Autophagy is the process by which cytoplasmic c...
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| Veröffentlicht in: | Autophagy 2014-07, Vol.10 (7), p.1272-1284 |
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| creator | Chen, Wei Zhang, Lisheng Zhang, Keqiang Zhou, Bingsen Kuo, Mei-Ling Hu, Shuya Chen, Linling Tang, Michelle Chen, Yun-Ru Yang, Lixin Ann, David K Yen, Yun |
| description | Ribonucleotide reductase (RNR) plays a critical role in catalyzing the biosynthesis and maintaining the intracellular concentration of 4 deoxyribonucleoside triphosphates (dNTPs). Unbalanced or deficient dNTP pools cause serious genotoxic consequences. Autophagy is the process by which cytoplasmic constituents are degraded in lysosomes to maintain cellular homeostasis and bioenergetics. However, the role of autophagy in regulating dNTP pools is not well understood. Herein, we reported that starvation- or rapamycin-induced autophagy was accompanied by a decrease in RNR activity and dNTP pools in human cancer cells. Furthermore, downregulation of the small subunit of RNR (RRM2) by siRNA or treatment with the RNR inhibitor hydroxyurea substantially induced autophagy. Conversely, cancer cells with abundant endogenous intracellular dNTPs or treated with dNTP precursors were less responsive to autophagy induction by rapamycin, suggesting that autophagy and dNTP pool levels are regulated through a negative feedback loop. Lastly, treatment with si-RRM2 caused an increase in MAP1LC3B, ATG5, BECN1, and ATG12 transcript abundance in xenografted Tu212 tumors in vivo. Together, our results revealed a previously unrecognized reciprocal regulation between dNTP pools and autophagy in cancer cells. |
| doi_str_mv | 10.4161/auto.28954 |
| format | Article |
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Unbalanced or deficient dNTP pools cause serious genotoxic consequences. Autophagy is the process by which cytoplasmic constituents are degraded in lysosomes to maintain cellular homeostasis and bioenergetics. However, the role of autophagy in regulating dNTP pools is not well understood. Herein, we reported that starvation- or rapamycin-induced autophagy was accompanied by a decrease in RNR activity and dNTP pools in human cancer cells. Furthermore, downregulation of the small subunit of RNR (RRM2) by siRNA or treatment with the RNR inhibitor hydroxyurea substantially induced autophagy. Conversely, cancer cells with abundant endogenous intracellular dNTPs or treated with dNTP precursors were less responsive to autophagy induction by rapamycin, suggesting that autophagy and dNTP pool levels are regulated through a negative feedback loop. Lastly, treatment with si-RRM2 caused an increase in MAP1LC3B, ATG5, BECN1, and ATG12 transcript abundance in xenografted Tu212 tumors in vivo. Together, our results revealed a previously unrecognized reciprocal regulation between dNTP pools and autophagy in cancer cells.</description><identifier>ISSN: 1554-8627</identifier><identifier>EISSN: 1554-8635</identifier><identifier>DOI: 10.4161/auto.28954</identifier><identifier>PMID: 24905824</identifier><language>eng</language><publisher>United States: Taylor & Francis</publisher><subject>Animals ; autophagy ; Autophagy - drug effects ; Basic Research Paper ; dNTP pools ; Gene Knockdown Techniques ; Humans ; Hydroxyurea - pharmacology ; Intracellular Space - drug effects ; Intracellular Space - metabolism ; Mice, Inbred NOD ; Mice, SCID ; Neoplasms - metabolism ; Neoplasms - pathology ; Nucleotides - metabolism ; rapamycin ; Ribonucleoside Diphosphate Reductase - metabolism ; ribonucleotide reductase ; RNA, Small Interfering - metabolism ; RRM2 ; Signal Transduction - drug effects ; Sirolimus - pharmacology ; Xenograft Model Antitumor Assays</subject><ispartof>Autophagy, 2014-07, Vol.10 (7), p.1272-1284</ispartof><rights>Copyright © 2014 Landes Bioscience 2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c424t-6302c161b31c0661fd06c09e4ac704c91a1d66cdda9a1cf613364dacf3e22b203</citedby><cites>FETCH-LOGICAL-c424t-6302c161b31c0661fd06c09e4ac704c91a1d66cdda9a1cf613364dacf3e22b203</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/PMC4203552/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4203552/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24905824$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chen, Wei</creatorcontrib><creatorcontrib>Zhang, Lisheng</creatorcontrib><creatorcontrib>Zhang, Keqiang</creatorcontrib><creatorcontrib>Zhou, Bingsen</creatorcontrib><creatorcontrib>Kuo, Mei-Ling</creatorcontrib><creatorcontrib>Hu, Shuya</creatorcontrib><creatorcontrib>Chen, Linling</creatorcontrib><creatorcontrib>Tang, Michelle</creatorcontrib><creatorcontrib>Chen, Yun-Ru</creatorcontrib><creatorcontrib>Yang, Lixin</creatorcontrib><creatorcontrib>Ann, David K</creatorcontrib><creatorcontrib>Yen, Yun</creatorcontrib><title>Reciprocal regulation of autophagy and dNTP pools in human cancer cells</title><title>Autophagy</title><addtitle>Autophagy</addtitle><description>Ribonucleotide reductase (RNR) plays a critical role in catalyzing the biosynthesis and maintaining the intracellular concentration of 4 deoxyribonucleoside triphosphates (dNTPs). Unbalanced or deficient dNTP pools cause serious genotoxic consequences. Autophagy is the process by which cytoplasmic constituents are degraded in lysosomes to maintain cellular homeostasis and bioenergetics. However, the role of autophagy in regulating dNTP pools is not well understood. Herein, we reported that starvation- or rapamycin-induced autophagy was accompanied by a decrease in RNR activity and dNTP pools in human cancer cells. Furthermore, downregulation of the small subunit of RNR (RRM2) by siRNA or treatment with the RNR inhibitor hydroxyurea substantially induced autophagy. Conversely, cancer cells with abundant endogenous intracellular dNTPs or treated with dNTP precursors were less responsive to autophagy induction by rapamycin, suggesting that autophagy and dNTP pool levels are regulated through a negative feedback loop. Lastly, treatment with si-RRM2 caused an increase in MAP1LC3B, ATG5, BECN1, and ATG12 transcript abundance in xenografted Tu212 tumors in vivo. Together, our results revealed a previously unrecognized reciprocal regulation between dNTP pools and autophagy in cancer cells.</description><subject>Animals</subject><subject>autophagy</subject><subject>Autophagy - drug effects</subject><subject>Basic Research Paper</subject><subject>dNTP pools</subject><subject>Gene Knockdown Techniques</subject><subject>Humans</subject><subject>Hydroxyurea - pharmacology</subject><subject>Intracellular Space - drug effects</subject><subject>Intracellular Space - metabolism</subject><subject>Mice, Inbred NOD</subject><subject>Mice, SCID</subject><subject>Neoplasms - metabolism</subject><subject>Neoplasms - pathology</subject><subject>Nucleotides - metabolism</subject><subject>rapamycin</subject><subject>Ribonucleoside Diphosphate Reductase - metabolism</subject><subject>ribonucleotide reductase</subject><subject>RNA, Small Interfering - metabolism</subject><subject>RRM2</subject><subject>Signal Transduction - drug effects</subject><subject>Sirolimus - pharmacology</subject><subject>Xenograft Model Antitumor Assays</subject><issn>1554-8627</issn><issn>1554-8635</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>0YH</sourceid><sourceid>EIF</sourceid><recordid>eNptkMtqGzEUQEVpiFMnm35A0bIE7Ohtz6ZQQpoETBKKsxbXksZW0UhTaSbFf59x7ZoUspJAR0dXB6HPlEwFVfQK-i5N2byS4gM6o1KKyVxx-fG4Z7MR-lTKL0K4mlfsFI2YqIicM3GGbn8649ucDASc3boP0PkUcarxztpuYL3FEC22D8sn3KYUCvYRb_oGIjYQjcvYuBDKOTqpIRR3cVjH6PnHzfL6brJ4vL2__r6YGMFEN1GcMDPMvOLUEKVobYkypHICzIwIU1GgViljLVRATa0o50pYMDV3jK0Y4WP0be9t-1XjrHGxyxB0m30DeasTeP3_SfQbvU4vWgyXpWSD4OtBkNPv3pVON77svgDRpb5oKgVns0ooOaCXe9TkVEp29fEZSvSuvN410n_LD_CXt4Md0X-pB0DuAR_rlBv4k3KwuoNtSLnOQ0pfNH9H_ArPhpLD</recordid><startdate>20140701</startdate><enddate>20140701</enddate><creator>Chen, Wei</creator><creator>Zhang, Lisheng</creator><creator>Zhang, Keqiang</creator><creator>Zhou, Bingsen</creator><creator>Kuo, Mei-Ling</creator><creator>Hu, Shuya</creator><creator>Chen, Linling</creator><creator>Tang, Michelle</creator><creator>Chen, Yun-Ru</creator><creator>Yang, Lixin</creator><creator>Ann, David K</creator><creator>Yen, Yun</creator><general>Taylor & Francis</general><general>Landes Bioscience</general><scope>0YH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20140701</creationdate><title>Reciprocal regulation of autophagy and dNTP pools in human cancer cells</title><author>Chen, Wei ; Zhang, Lisheng ; Zhang, Keqiang ; Zhou, Bingsen ; Kuo, Mei-Ling ; Hu, Shuya ; Chen, Linling ; Tang, Michelle ; Chen, Yun-Ru ; Yang, Lixin ; Ann, David K ; Yen, Yun</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c424t-6302c161b31c0661fd06c09e4ac704c91a1d66cdda9a1cf613364dacf3e22b203</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Animals</topic><topic>autophagy</topic><topic>Autophagy - drug effects</topic><topic>Basic Research Paper</topic><topic>dNTP pools</topic><topic>Gene Knockdown Techniques</topic><topic>Humans</topic><topic>Hydroxyurea - pharmacology</topic><topic>Intracellular Space - drug effects</topic><topic>Intracellular Space - metabolism</topic><topic>Mice, Inbred NOD</topic><topic>Mice, SCID</topic><topic>Neoplasms - metabolism</topic><topic>Neoplasms - pathology</topic><topic>Nucleotides - metabolism</topic><topic>rapamycin</topic><topic>Ribonucleoside Diphosphate Reductase - metabolism</topic><topic>ribonucleotide reductase</topic><topic>RNA, Small Interfering - metabolism</topic><topic>RRM2</topic><topic>Signal Transduction - drug effects</topic><topic>Sirolimus - pharmacology</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chen, Wei</creatorcontrib><creatorcontrib>Zhang, Lisheng</creatorcontrib><creatorcontrib>Zhang, Keqiang</creatorcontrib><creatorcontrib>Zhou, Bingsen</creatorcontrib><creatorcontrib>Kuo, Mei-Ling</creatorcontrib><creatorcontrib>Hu, Shuya</creatorcontrib><creatorcontrib>Chen, Linling</creatorcontrib><creatorcontrib>Tang, Michelle</creatorcontrib><creatorcontrib>Chen, Yun-Ru</creatorcontrib><creatorcontrib>Yang, Lixin</creatorcontrib><creatorcontrib>Ann, David K</creatorcontrib><creatorcontrib>Yen, Yun</creatorcontrib><collection>Taylor & Francis Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Autophagy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chen, Wei</au><au>Zhang, Lisheng</au><au>Zhang, Keqiang</au><au>Zhou, Bingsen</au><au>Kuo, Mei-Ling</au><au>Hu, Shuya</au><au>Chen, Linling</au><au>Tang, Michelle</au><au>Chen, Yun-Ru</au><au>Yang, Lixin</au><au>Ann, David K</au><au>Yen, Yun</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Reciprocal regulation of autophagy and dNTP pools in human cancer cells</atitle><jtitle>Autophagy</jtitle><addtitle>Autophagy</addtitle><date>2014-07-01</date><risdate>2014</risdate><volume>10</volume><issue>7</issue><spage>1272</spage><epage>1284</epage><pages>1272-1284</pages><issn>1554-8627</issn><eissn>1554-8635</eissn><abstract>Ribonucleotide reductase (RNR) plays a critical role in catalyzing the biosynthesis and maintaining the intracellular concentration of 4 deoxyribonucleoside triphosphates (dNTPs). Unbalanced or deficient dNTP pools cause serious genotoxic consequences. Autophagy is the process by which cytoplasmic constituents are degraded in lysosomes to maintain cellular homeostasis and bioenergetics. However, the role of autophagy in regulating dNTP pools is not well understood. Herein, we reported that starvation- or rapamycin-induced autophagy was accompanied by a decrease in RNR activity and dNTP pools in human cancer cells. Furthermore, downregulation of the small subunit of RNR (RRM2) by siRNA or treatment with the RNR inhibitor hydroxyurea substantially induced autophagy. Conversely, cancer cells with abundant endogenous intracellular dNTPs or treated with dNTP precursors were less responsive to autophagy induction by rapamycin, suggesting that autophagy and dNTP pool levels are regulated through a negative feedback loop. Lastly, treatment with si-RRM2 caused an increase in MAP1LC3B, ATG5, BECN1, and ATG12 transcript abundance in xenografted Tu212 tumors in vivo. Together, our results revealed a previously unrecognized reciprocal regulation between dNTP pools and autophagy in cancer cells.</abstract><cop>United States</cop><pub>Taylor & Francis</pub><pmid>24905824</pmid><doi>10.4161/auto.28954</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Autophagy, 2014-07, Vol.10 (7), p.1272-1284 |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | Animals autophagy Autophagy - drug effects Basic Research Paper dNTP pools Gene Knockdown Techniques Humans Hydroxyurea - pharmacology Intracellular Space - drug effects Intracellular Space - metabolism Mice, Inbred NOD Mice, SCID Neoplasms - metabolism Neoplasms - pathology Nucleotides - metabolism rapamycin Ribonucleoside Diphosphate Reductase - metabolism ribonucleotide reductase RNA, Small Interfering - metabolism RRM2 Signal Transduction - drug effects Sirolimus - pharmacology Xenograft Model Antitumor Assays |
| title | Reciprocal regulation of autophagy and dNTP pools in human cancer cells |
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