PDE5 inhibition eliminates cancer stem cells via induction of PKA signaling
Cancer stem cells (CSCs) are involved in metastasis and resistance development, thus affecting anticancer therapy efficacy. The underlying pathways required for CSC maintenance and survival are not fully understood and only a limited number of treatment strategies to specifically target CSCs have be...
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| Veröffentlicht in: | Cell death & disease 2018-02, Vol.9 (2), p.192-15, Article 192 |
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| creator | Klutzny, Saskia Anurin, Anna Nicke, Barbara Regan, Joseph L. Lange, Martin Schulze, Luise Parczyk, Karsten Steigemann, Patrick |
| description | Cancer stem cells (CSCs) are involved in metastasis and resistance development, thus affecting anticancer therapy efficacy. The underlying pathways required for CSC maintenance and survival are not fully understood and only a limited number of treatment strategies to specifically target CSCs have been identified. To identify novel CSC targeting compounds, we here set-up an aldehyde dehydrogenase (ALDH)-based phenotypic screening system that allows for an automated and standardized identification of CSCs. By staining cancer cells for ALDH activity and applying high-content-based single-cell population analysis, the proportion of a potential CSC subpopulation with significantly higher ALDH activity (ALDH
high
) can be quantified in a heterogeneous cell population. We confirmed high ALDH activity as surrogate marker for the CSC subpopulation
in vitro
and validated Wnt signaling as an essential factor for the maintenance of CSCs in SUM149 breast cancer cells. In a small molecule screen, we identified phosphodiesterase type 5 (PDE5) inhibition as potential strategy to target CSC maintenance and survival in multiple cancer cell lines. CSC elimination by PDE5 inhibition was not dependent on PKG signaling, and we suggest a novel mechanism in which PDE5 inhibition leads to elevated cGMP levels that stimulate cAMP/PKA signaling to eliminate CSCs. |
| doi_str_mv | 10.1038/s41419-017-0202-5 |
| format | Article |
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high
) can be quantified in a heterogeneous cell population. We confirmed high ALDH activity as surrogate marker for the CSC subpopulation
in vitro
and validated Wnt signaling as an essential factor for the maintenance of CSCs in SUM149 breast cancer cells. In a small molecule screen, we identified phosphodiesterase type 5 (PDE5) inhibition as potential strategy to target CSC maintenance and survival in multiple cancer cell lines. CSC elimination by PDE5 inhibition was not dependent on PKG signaling, and we suggest a novel mechanism in which PDE5 inhibition leads to elevated cGMP levels that stimulate cAMP/PKA signaling to eliminate CSCs.</description><identifier>ISSN: 2041-4889</identifier><identifier>EISSN: 2041-4889</identifier><identifier>DOI: 10.1038/s41419-017-0202-5</identifier><identifier>PMID: 29416006</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>14/34 ; 14/63 ; 38/39 ; 38/89 ; 96/31 ; Aldehyde dehydrogenase ; Antibodies ; Biochemistry ; Biomedical and Life Sciences ; Breast cancer ; Cancer ; Cell Biology ; Cell Culture ; Cell survival ; Cyclic GMP ; Immunology ; Kinases ; Life Sciences ; Metastases ; Phosphodiesterase ; Protein kinase A ; Stem cells ; Tumor cell lines ; Wnt protein</subject><ispartof>Cell death & disease, 2018-02, Vol.9 (2), p.192-15, Article 192</ispartof><rights>The Author(s) 2018</rights><rights>2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c536t-c7b1e9383c770aeff4636f4721d924b48d6ac548cb70066497e63118974761fe3</citedby><cites>FETCH-LOGICAL-c536t-c7b1e9383c770aeff4636f4721d924b48d6ac548cb70066497e63118974761fe3</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/PMC5833477/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833477/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,27924,27925,41120,42189,51576,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29416006$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Klutzny, Saskia</creatorcontrib><creatorcontrib>Anurin, Anna</creatorcontrib><creatorcontrib>Nicke, Barbara</creatorcontrib><creatorcontrib>Regan, Joseph L.</creatorcontrib><creatorcontrib>Lange, Martin</creatorcontrib><creatorcontrib>Schulze, Luise</creatorcontrib><creatorcontrib>Parczyk, Karsten</creatorcontrib><creatorcontrib>Steigemann, Patrick</creatorcontrib><title>PDE5 inhibition eliminates cancer stem cells via induction of PKA signaling</title><title>Cell death & disease</title><addtitle>Cell Death Dis</addtitle><addtitle>Cell Death Dis</addtitle><description>Cancer stem cells (CSCs) are involved in metastasis and resistance development, thus affecting anticancer therapy efficacy. The underlying pathways required for CSC maintenance and survival are not fully understood and only a limited number of treatment strategies to specifically target CSCs have been identified. To identify novel CSC targeting compounds, we here set-up an aldehyde dehydrogenase (ALDH)-based phenotypic screening system that allows for an automated and standardized identification of CSCs. By staining cancer cells for ALDH activity and applying high-content-based single-cell population analysis, the proportion of a potential CSC subpopulation with significantly higher ALDH activity (ALDH
high
) can be quantified in a heterogeneous cell population. We confirmed high ALDH activity as surrogate marker for the CSC subpopulation
in vitro
and validated Wnt signaling as an essential factor for the maintenance of CSCs in SUM149 breast cancer cells. In a small molecule screen, we identified phosphodiesterase type 5 (PDE5) inhibition as potential strategy to target CSC maintenance and survival in multiple cancer cell lines. CSC elimination by PDE5 inhibition was not dependent on PKG signaling, and we suggest a novel mechanism in which PDE5 inhibition leads to elevated cGMP levels that stimulate cAMP/PKA signaling to eliminate CSCs.</description><subject>14/34</subject><subject>14/63</subject><subject>38/39</subject><subject>38/89</subject><subject>96/31</subject><subject>Aldehyde dehydrogenase</subject><subject>Antibodies</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Breast cancer</subject><subject>Cancer</subject><subject>Cell Biology</subject><subject>Cell Culture</subject><subject>Cell survival</subject><subject>Cyclic GMP</subject><subject>Immunology</subject><subject>Kinases</subject><subject>Life Sciences</subject><subject>Metastases</subject><subject>Phosphodiesterase</subject><subject>Protein kinase A</subject><subject>Stem cells</subject><subject>Tumor cell lines</subject><subject>Wnt protein</subject><issn>2041-4889</issn><issn>2041-4889</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp1kUlLBDEQhYMoKjo_wIs0ePHSmqU6y0UQdxScg55DOpMeI91pTboF_70Zxx2sSwrqq5d6PIR2CD4gmMnDBASIKjERJaaYltUK2qQYSAlSqtUf_QaapPSIczGGacXX0QZVQDjGfBNdT0_PqsKHB1_7wfehcK3vfDCDS4U1wbpYpMF1hXVtm4oXbzI7G-072jfF9Pq4SH4eTOvDfButNaZNbvLxbqH787O7k8vy5vbi6uT4prQV40NpRU2cYpJZIbBxTQOc8QYEJTNFoQY548ZWIG0t8okclHCcESKVAMFJ49gWOlrqPo1152bWhSGaVj9F35n4qnvj9e9J8A963r_oSjIGQmSB_Q-B2D-PLg2682nh0ATXj0kTpRSXgNkC3fuDPvZjzH6TppgoAI4ryBRZUjb2KUXXfB1DsF6kpZdp6ZyWXqSlq7yz-9PF18ZnNhmgSyDlUZi7-P31_6pv9QKd_g</recordid><startdate>20180207</startdate><enddate>20180207</enddate><creator>Klutzny, Saskia</creator><creator>Anurin, Anna</creator><creator>Nicke, Barbara</creator><creator>Regan, Joseph L.</creator><creator>Lange, Martin</creator><creator>Schulze, Luise</creator><creator>Parczyk, Karsten</creator><creator>Steigemann, Patrick</creator><general>Nature Publishing Group UK</general><general>Springer Nature B.V</general><scope>C6C</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88I</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M2P</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20180207</creationdate><title>PDE5 inhibition eliminates cancer stem cells via induction of PKA signaling</title><author>Klutzny, Saskia ; 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The underlying pathways required for CSC maintenance and survival are not fully understood and only a limited number of treatment strategies to specifically target CSCs have been identified. To identify novel CSC targeting compounds, we here set-up an aldehyde dehydrogenase (ALDH)-based phenotypic screening system that allows for an automated and standardized identification of CSCs. By staining cancer cells for ALDH activity and applying high-content-based single-cell population analysis, the proportion of a potential CSC subpopulation with significantly higher ALDH activity (ALDH
high
) can be quantified in a heterogeneous cell population. We confirmed high ALDH activity as surrogate marker for the CSC subpopulation
in vitro
and validated Wnt signaling as an essential factor for the maintenance of CSCs in SUM149 breast cancer cells. In a small molecule screen, we identified phosphodiesterase type 5 (PDE5) inhibition as potential strategy to target CSC maintenance and survival in multiple cancer cell lines. CSC elimination by PDE5 inhibition was not dependent on PKG signaling, and we suggest a novel mechanism in which PDE5 inhibition leads to elevated cGMP levels that stimulate cAMP/PKA signaling to eliminate CSCs.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>29416006</pmid><doi>10.1038/s41419-017-0202-5</doi><tpages>15</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 14/34 14/63 38/39 38/89 96/31 Aldehyde dehydrogenase Antibodies Biochemistry Biomedical and Life Sciences Breast cancer Cancer Cell Biology Cell Culture Cell survival Cyclic GMP Immunology Kinases Life Sciences Metastases Phosphodiesterase Protein kinase A Stem cells Tumor cell lines Wnt protein |
| title | PDE5 inhibition eliminates cancer stem cells via induction of PKA signaling |
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