Studies of Non-Protective Autophagy Provide Evidence that Recovery from Therapy-Induced Senescence is Independent of Early Autophagy
Identifieur interne : 000628 ( Pmc/Curation ); précédent : 000627; suivant : 000629Studies of Non-Protective Autophagy Provide Evidence that Recovery from Therapy-Induced Senescence is Independent of Early Autophagy
Auteurs : Tareq Saleh ; Liliya Tyutyunyk-Massey [États-Unis] ; Nipa H. Patel [États-Unis] ; Emmanuel K. Cudjoe ; Moureq Alotaibi ; David A. Gewirtz [États-Unis]Source :
- International Journal of Molecular Sciences [ 1422-0067 ] ; 2020.
Abstract
Autophagy and senescence, predominant responses that may dictate cell fate after chemotherapy or radiation, often occur in tandem. Cells in states of senescence and/or autophagy are frequently growth arrested. We have previously reported that tumor cells induced into senescence by therapy can re-emerge from the growth-arrested state, a phenomenon termed proliferative recovery. The current work shows that, while tumor cells collaterally induced into senescence and autophagy by etoposide, doxorubicin, or radiation undergo proliferative recovery, neither pharmacological nor genetic inhibition of early autophagy alter the extent of senescence or the ability of cells to recover from senescence. These findings confirm and extend our previous observations, essentially dissociating senescence from autophagy, and further indicate that re-emergence from senescence does not appear to be facilitated by or dependent on autophagy. Our results also provide additional evidence for the promotion of the non-protective form of autophagy by both chemotherapeutic drugs and radiation, which may complicate current efforts to inhibit autophagy for therapeutic benefit.
Url:
DOI: 10.3390/ijms21041427
PubMed: 32093197
PubMed Central: 7073138
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Patel">Nipa H. Patel</name><affiliation><nlm:aff id="af2-ijms-21-01427">Massey Cancer Center, Goodwin Research Laboratories, Virginia Commonwealth University, Richmond, VA 23298, USA;<email>tyutyunykmals@vcu.edu</email> (L.T.-M.);<email>patelnh3@vcu.edu</email> (N.H.P.)</nlm:aff></affiliation><affiliation wicri:level="1"><nlm:aff id="af3-ijms-21-01427">Department of Pharmacology and Toxicology and Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pharmacology and Toxicology and Medicine, Virginia Commonwealth University, Richmond, VA 23298</wicri:regionArea></affiliation></author><author><name sortKey="K Cudjoe, Emmanuel" sort="K Cudjoe, Emmanuel" uniqKey="K Cudjoe E" first="Emmanuel" last="K. Cudjoe">Emmanuel K. Cudjoe</name><affiliation><nlm:aff id="af4-ijms-21-01427">Department of Pharmacotherapy & Outcomes Science, Virginia Commonwealth University, Richmond, VA 23298, USA;<email>cudjoeek@vcu.edu</email></nlm:aff></affiliation></author><author><name sortKey="Alotaibi, Moureq" sort="Alotaibi, Moureq" uniqKey="Alotaibi M" first="Moureq" last="Alotaibi">Moureq Alotaibi</name><affiliation><nlm:aff id="af5-ijms-21-01427">College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia;<email>mralotaibi@ksu.edu.sa</email></nlm:aff></affiliation></author><author><name sortKey="A Gewirtz, David" sort="A Gewirtz, David" uniqKey="A Gewirtz D" first="David" last="A. Gewirtz">David A. Gewirtz</name><affiliation><nlm:aff id="af2-ijms-21-01427">Massey Cancer Center, Goodwin Research Laboratories, Virginia Commonwealth University, Richmond, VA 23298, USA;<email>tyutyunykmals@vcu.edu</email> (L.T.-M.);<email>patelnh3@vcu.edu</email> (N.H.P.)</nlm:aff></affiliation><affiliation wicri:level="1"><nlm:aff id="af3-ijms-21-01427">Department of Pharmacology and Toxicology and Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pharmacology and Toxicology and Medicine, Virginia Commonwealth University, Richmond, VA 23298</wicri:regionArea></affiliation></author></analytic><series><title level="j">International Journal of Molecular Sciences</title><idno type="eISSN">1422-0067</idno><imprint><date when="2020">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Autophagy and senescence, predominant responses that may dictate cell fate after chemotherapy or radiation, often occur in tandem. Cells in states of senescence and/or autophagy are frequently growth arrested. We have previously reported that tumor cells induced into senescence by therapy can re-emerge from the growth-arrested state, a phenomenon termed proliferative recovery. The current work shows that, while tumor cells collaterally induced into senescence and autophagy by etoposide, doxorubicin, or radiation undergo proliferative recovery, neither pharmacological nor genetic inhibition of early autophagy alter the extent of senescence or the ability of cells to recover from senescence. These findings confirm and extend our previous observations, essentially dissociating senescence from autophagy, and further indicate that re-emergence from senescence does not appear to be facilitated by or dependent on autophagy. Our results also provide additional evidence for the promotion of the non-protective form of autophagy by both chemotherapeutic drugs and radiation, which may complicate current efforts to inhibit autophagy for therapeutic benefit.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Ewald, J A" uniqKey="Ewald J">J.A. Ewald</name></author><author><name sortKey="Desotelle, J A" uniqKey="Desotelle J">J.A. Desotelle</name></author><author><name sortKey="Wilding, G" uniqKey="Wilding G">G. Wilding</name></author><author><name sortKey="Jarrard, D F" uniqKey="Jarrard D">D.F. Jarrard</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gewirtz, D A" uniqKey="Gewirtz D">D.A. Gewirtz</name></author><author><name sortKey="Holt, S E" uniqKey="Holt S">S.E. Holt</name></author><author><name sortKey="Elmore, L W" uniqKey="Elmore L">L.W. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Int J Mol Sci</journal-id><journal-id journal-id-type="iso-abbrev">Int J Mol Sci</journal-id><journal-id journal-id-type="publisher-id">ijms</journal-id><journal-title-group><journal-title>International Journal of Molecular Sciences</journal-title></journal-title-group><issn pub-type="epub">1422-0067</issn><publisher><publisher-name>MDPI</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">32093197</article-id><article-id pub-id-type="pmc">7073138</article-id><article-id pub-id-type="doi">10.3390/ijms21041427</article-id><article-id pub-id-type="publisher-id">ijms-21-01427</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Studies of Non-Protective Autophagy Provide Evidence that Recovery from Therapy-Induced Senescence is Independent of Early Autophagy</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Saleh</surname><given-names>Tareq</given-names></name><xref ref-type="aff" rid="af1-ijms-21-01427">1</xref><xref ref-type="aff" rid="af2-ijms-21-01427">2</xref></contrib><contrib contrib-type="author"><name><surname>Tyutyunyk-Massey</surname><given-names>Liliya</given-names></name><xref ref-type="aff" rid="af2-ijms-21-01427">2</xref><xref ref-type="aff" rid="af3-ijms-21-01427">3</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-2183-3170</contrib-id><name><surname>H. Patel</surname><given-names>Nipa</given-names></name><xref ref-type="aff" rid="af2-ijms-21-01427">2</xref><xref ref-type="aff" rid="af3-ijms-21-01427">3</xref></contrib><contrib contrib-type="author"><name><surname>K. Cudjoe</surname><given-names>Emmanuel</given-names><suffix>Jr.</suffix></name><xref ref-type="aff" rid="af4-ijms-21-01427">4</xref></contrib><contrib contrib-type="author"><name><surname>Alotaibi</surname><given-names>Moureq</given-names></name><xref ref-type="aff" rid="af5-ijms-21-01427">5</xref></contrib><contrib contrib-type="author"><name><surname>A. Gewirtz</surname><given-names>David</given-names></name><xref ref-type="aff" rid="af2-ijms-21-01427">2</xref><xref ref-type="aff" rid="af3-ijms-21-01427">3</xref><xref rid="c1-ijms-21-01427" ref-type="corresp">*</xref></contrib></contrib-group><aff id="af1-ijms-21-01427"><label>1</label>Department of Basic Medical Sciences, Faculty of Medicine, The Hashemite University, Zarqa 13133, Jordan;<email>tareq@hu.edu.jo</email></aff><aff id="af2-ijms-21-01427"><label>2</label>Massey Cancer Center, Goodwin Research Laboratories, Virginia Commonwealth University, Richmond, VA 23298, USA;<email>tyutyunykmals@vcu.edu</email> (L.T.-M.);<email>patelnh3@vcu.edu</email> (N.H.P.)</aff><aff id="af3-ijms-21-01427"><label>3</label>Department of Pharmacology and Toxicology and Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA</aff><aff id="af4-ijms-21-01427"><label>4</label>Department of Pharmacotherapy & Outcomes Science, Virginia Commonwealth University, Richmond, VA 23298, USA;<email>cudjoeek@vcu.edu</email></aff><aff id="af5-ijms-21-01427"><label>5</label>College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia;<email>mralotaibi@ksu.edu.sa</email></aff><author-notes><corresp id="c1-ijms-21-01427"><label>*</label>Correspondence: <email>david.gewirtz@vcuhealth.org</email></corresp></author-notes><pub-date pub-type="epub"><day>20</day><month>2</month><year>2020</year></pub-date><pub-date pub-type="collection"><month>2</month><year>2020</year></pub-date><volume>21</volume><issue>4</issue><elocation-id>1427</elocation-id><history><date date-type="received"><day>12</day><month>10</month><year>2019</year></date><date date-type="accepted"><day>11</day><month>2</month><year>2020</year></date></history><permissions><copyright-statement>© 2020 by the authors.</copyright-statement><copyright-year>2020</copyright-year><license license-type="open-access"><license-p>Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>).</license-p></license></permissions><abstract><p>Autophagy and senescence, predominant responses that may dictate cell fate after chemotherapy or radiation, often occur in tandem. Cells in states of senescence and/or autophagy are frequently growth arrested. We have previously reported that tumor cells induced into senescence by therapy can re-emerge from the growth-arrested state, a phenomenon termed proliferative recovery. The current work shows that, while tumor cells collaterally induced into senescence and autophagy by etoposide, doxorubicin, or radiation undergo proliferative recovery, neither pharmacological nor genetic inhibition of early autophagy alter the extent of senescence or the ability of cells to recover from senescence. These findings confirm and extend our previous observations, essentially dissociating senescence from autophagy, and further indicate that re-emergence from senescence does not appear to be facilitated by or dependent on autophagy. Our results also provide additional evidence for the promotion of the non-protective form of autophagy by both chemotherapeutic drugs and radiation, which may complicate current efforts to inhibit autophagy for therapeutic benefit.</p></abstract><kwd-group><kwd>senescence</kwd><kwd>autophagy</kwd><kwd>cancer</kwd><kwd>chemotherapy</kwd><kwd>radiotherapy</kwd><kwd>proliferative recovery</kwd></kwd-group></article-meta></front><floats-group><fig id="ijms-21-01427-f001" orientation="portrait" position="float"><label>Figure 1</label><caption><p>The induction of senescence and autophagy in H460 cells in response to etoposide. (<bold>A</bold>) Senescence-associated β-galactosidase staining of H460 cells exposed to etoposide (0.25, 0.5, or 1 µM) 48 h after drug removal (20x objective). (<bold>B</bold>) Quantification of senescence based on C<sub>12</sub>FDG staining of H460 cells followed by fluorescence-activated cell sorting (FACS) analysis. (<bold>C</bold>) Widefield fluorescent microscopy showing C<sub>12</sub>FDG staining. Nuclei stained with Hoechst 33342 (20x objective). Staining and analysis were performed 48 h after drug removal (<bold>D</bold>) Growth arrest and proliferative recovery of H460 cells exposed to etoposide (1 µM) for 24 h (day 0). (<bold>E</bold>) Fluorescence microscopy showing concentration-dependent increase in acridine orange-stained vacuoles induced by 0.25, 0.5, and 1 µM etoposide (20x objective). (<bold>F</bold>) Quantification of acidic vesicular organelles (AVOs) by FACS analysis in response to increasing concentrations of etoposide. (<bold>G</bold>) Fluorescence microscopy showing increased GFP-LC3 puncta in response to etoposide (1 µM) exposure. Imaging performed 48 h after drug removal. (20x objective). Quantification of GFP-LC3 puncta formation in response to etoposide exposure. Results presented were from three independent experiments, unless otherwise indicated. *<italic>p</italic> < 0.05 compared to untreated controls.</p></caption><graphic xlink:href="ijms-21-01427-g001"></graphic></fig><fig id="ijms-21-01427-f002" orientation="portrait" position="float"><label>Figure 2</label><caption><p>Inhibition of autophagy does not interfere with the induction or the recovery from senescence in H460 cells exposed to etoposide. (<bold>A</bold>) Fluorescence microscopy showing failure of lysosomal acidification following chloroquine (CQ, 10 µM) or bafilomycin A1 (Baf, 5 nM) co-treatment with etoposide (ETO, 1 µM). Cells were pretreated with CQ and Baf followed by an additional 24 h with etoposide. Images were taken 48 h after drug removal. Nuclei stained with Hoechst 33342 (20x objective). (<bold>B</bold>) Western blot showing autophagy blockade by CQ (10 µM) and Baf (5 nM) based on levels of p62/SQSTM1 (<bold>C</bold>) Clonogenic survival assay showing influence of CQ (10 µM) or Baf (5 nM) on sensitivity of H460 cells to etoposide. Cells were pretreated with CQ or Baf for 3 h followed by co-treatment with etoposide for 24 h. Colonies were counted 7 days following removal of drugs and replacement with fresh medium. Bars represent mean survival ± SD relative to untreated controls (α = 0.05/3, * <italic>p</italic> < 0.016). (<bold>D</bold>) and (<bold>E</bold>) Temporal response to etoposide in H460 cells after pharmacological autophagy inhibition. Viable H460 cell number was determined at the indicated days following etoposide exposure in combination with 10 µM CQ (D) or 5 nM Baf (<bold>E</bold>). (<bold>F</bold>) Assessment of apoptosis 48 h after drug removal (n.s. = no significant difference). (<bold>G</bold>) Western blot following short hairpin RNA (shRNA)-mediated knockdown of Atg5. (<bold>H</bold>) Clonogenic survival assay comparing sensitivity of shControl and shAtg5 H460 cells in response to multiple etoposide concentrations. Bars represent mean survival ± SD relative to untreated controls (α = 0.05/3, * <italic>p</italic> < 0.016). (<bold>I</bold>) Temporal response to etoposide in shControl H460 cells and H460 cells with knockdown of Atg5. (<bold>J</bold>) Etoposide-induced senescence in both autophagy-proficient and autophagy-deficient H460 cells by staining for SA-β-gal activity (20x objective). (<bold>K</bold>) Percent senescence based on C<sub>12</sub>FDG staining at day 3 post-etoposide exposure in shControl cells and shAtg5 cells. Results presented were from three independent experiments unless otherwise indicated.</p></caption><graphic xlink:href="ijms-21-01427-g002"></graphic></fig><fig id="ijms-21-01427-f003" orientation="portrait" position="float"><label>Figure 3</label><caption><p>The induction of senescence and autophagy in 4T1 cells in response to doxorubicin (<bold>A</bold>) Induction of senescence determined by elevated senescence-associated β-galactosidase staining in 4T1 cells treated with 1 µM doxorubicin (Dox) for 2 hours (20x objective). (<bold>B</bold>) Quantification of senescence by FACS analysis based on C<sub>12</sub>FDG staining of 4T1 cells. (<bold>C</bold>) Fluorescence microscopy images showing an increase in acridine orange staining in cells treated with Dox (1 µM). 4T1 cells were pre-treated with CQ (10 µM) for 3 hours followed by 2 hour exposure to Dox with or without CQ (20x objective). (<bold>D</bold>) Quantification of autophagic cells by FACS analysis in response to Dox treatment showing accumulation of acridine orange (AO) positive cells that is further enhanced by inhibition of acidic degradation by CQ. (<bold>E</bold>) Induction of autophagy confirmed by Western Blot showing degradation of p62/SQSTM1 protein following a 2 h exposure to Dox (1 µM). (<bold>F</bold>) Blockade of autophagic flux by chloroquine resulting in accumulation of LC3BII protein. *<italic>p</italic> < 0.05 compared to untreated controls.</p></caption><graphic xlink:href="ijms-21-01427-g003"></graphic></fig><fig id="ijms-21-01427-f004" orientation="portrait" position="float"><label>Figure 4</label><caption><p>Inhibition of autophagy does not interfere with the induction or the recovery from senescence in 4T1 cells exposed to doxorubicin (<bold>A</bold>) Temporal response to Dox (1 µM) in 4T1 cells after pharmacological inhibition of autophagy with CQ. Viable cell number was determined at the indicated time points after treatment with Dox in combination with CQ (10 µM). Adjoining figure shows expanded scale for lower portion of the graph. (<bold>B</bold>) Knockdown of Atg5 in 4T1 cells confirmed by Western blot. (<bold>C</bold>) Western blot of Atg5 deficient 4T1 exposed to Dox showing conversion of LC3BI to LC3BII in WT cells, accumulation of LC3BI with decreased LC3BII in autophagy deficient cells. (<bold>D</bold>) Assessment of apoptosis by FACS analysis 24 hours post-treatment with Dox using APC/7AAD [Annexin 5/propidium iodide (PI) equivalent] dye. Genetic inhibition of autophagy did not result in increased apoptosis. (<bold>E</bold>) Colony formation assay comparing clonogenic survival of shControl and shAtg5 4T1 cells in response to multiple Dox concentrations. (<bold>F</bold>) Induction of senescence determined by SA-β-gal staining in shControl and shAtg5 4T1 cells treated with 1 µM Dox (20x objective). (<bold>G</bold>) Percent senescence based on quantification of C<sub>12</sub>FDG staining 48 hours after exposure of shControl cells and shAtg5 cells to Dox. (<bold>H</bold>) Temporal assessment of growth arrest followed by proliferative recovery in shControl and shAtg5 4T1 cells. Viable cell number was determined at the indicated time points after treatment with doxorubicin. Adjoining figure shows expanded scale for lower portion of the graph. (n.s. = no significant difference).</p></caption><graphic xlink:href="ijms-21-01427-g004a"></graphic><graphic xlink:href="ijms-21-01427-g004b"></graphic></fig><fig id="ijms-21-01427-f005" orientation="portrait" position="float"><label>Figure 5</label><caption><p>The induction of senescence and autophagy in HCT116 cells in response to radiation. (<bold>A</bold>) SA- β-galactosidase staining of HCT116 cells treated with 4 Gy radiation demonstrating induction of senescence (20x objective). (<bold>B</bold>) Fluorescent microscopy images of acridine orange staining 48 hours post-radiation (4 Gy). Increased acidic vesicle formation is visualized (20x objective). C-G. Cells were pre-treated with CQ (5 µM) 3 h prior to radiation (4 Gy) exposure. Media was replenished 24 h post-treatment. (<bold>C</bold>) Western blot analysis demonstrating autophagy blockade via p62 accumulation in cells pre-treated with CQ. (<bold>D</bold>) Acridine orange staining indicating blockade of lysosomal fusion in cells pre-treated with CQ (20x objective). (<bold>E</bold>) SA-β-galactosidase staining demonstrating increased SA-β-galactosidase activity in both cells exposed to radiation alone or pre-treated with CQ prior to radiation (20x objective). (<bold>F</bold>) SA-β-galactosidase activity was monitored by measuring C<sub>12</sub>FDG staining using flow cytometry. (<bold>G</bold>) Clonogenic survival assay showing radiation-induced growth inhibition in cells exposed to radiation (4 Gy) alone and in combination with CQ (5 µM). (<bold>H</bold>) Annexin 5/PI staining was used to assess apoptosis 48 h post-radiation [radiation (4 Gy) alone or with CQ (5 µM) pre-treatment]. Autophagy blockade did not alter radiation-induced apoptosis (<italic>n</italic> = 2). (<bold>I</bold>) Cells were treated with 4 Gy radiation alone or with CQ pre-treatment, and viable cell number was assessed via trypan blue exclusion on the indicated days. The adjoining figure shows the expanded scale for the lower portion of the graph. (<bold>J</bold>) Western blot demonstrating ATG5 knockdown. Autophagy blockade by shATG5 in the HCT-116 cells was established in our previous report [<xref rid="B17-ijms-21-01427" ref-type="bibr">17</xref>]. (<bold>K</bold>) Clonogenic survival demonstrating dose-dependent reduction in both shControl and shATG5 knockdown cells. (<bold>L</bold>) Viable cell number was assessed in shControl and shATG5 HCT116 cells exposed to 4 Gy radiation. Representative curves of three independent studies are shown (<italic>n</italic> = 3). Results presented were from three independent experiments, unless otherwise indicated; n.s. represents no significant difference compared to radiation alone.</p></caption><graphic xlink:href="ijms-21-01427-g005"></graphic></fig><fig id="ijms-21-01427-f006" orientation="portrait" position="float"><label>Figure 6</label><caption><p>Early inhibition of non-protective autophagy does not interfere with recovery from therapy-induced senescence in tumor cells. Both senescence and autophagy are stress responses frequently induced in parallel in tumor cells exposed to DNA-damaging therapy. Therapy-induced senescence engenders a phase of stable growth arrest whereby a subpopulation of tumor cells can ultimately recover proliferative capacity. Autophagy induced in tumor cells in response to conventional chemotherapy or radiation takes on different functional outcomes. Of those, autophagy can be non-protective, meaning that when autophagy is blocked by pharmacological or genetic approaches, survival of tumor cells is not essentially affected. This figure illustrates how the inhibition of non-protective autophagy in therapy-induced senescent tumor cells does not interfere with tumor cell survival or the ability of these cells to recover from senescence.</p></caption><graphic xlink:href="ijms-21-01427-g006"></graphic></fig></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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