The SGK1 inhibitor SI113 induces autophagy, apoptosis, and endoplasmic reticulum stress in endometrial cancer cells
Endometrial cancer is often characterized by PI3K/AKT pathway deregulation. Recently it has been suggested that SGK1, a serine/threonine protein kinase that shares structural and functional similarities with the AKT family, might play a role in cancer, since its expression and/or activity has been f...
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| Veröffentlicht in: | Journal of cellular physiology 2017-12, Vol.232 (12), p.3735-3743 |
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| creator | Conza, Domenico Mirra, Paola Calì, Gaetano Tortora, Teresa Insabato, Luigi Fiory, Francesca Schenone, Silvia Amato, Rosario Beguinot, Francesco Perrotti, Nicola Ulianich, Luca |
| description | Endometrial cancer is often characterized by PI3K/AKT pathway deregulation. Recently it has been suggested that SGK1, a serine/threonine protein kinase that shares structural and functional similarities with the AKT family, might play a role in cancer, since its expression and/or activity has been found to be deregulated in different human tumors. However, the role of SGK1 in endometrial cancer has been poorly investigated. Here, we show that SGK1 expression is increased in tissue specimens from neoplastic endometrium. The SGK1 inhibitor SI113 induced a significant reduction of endometrial cancer cells viability, measured by the (3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyl tetrazolium bromide assay. This effect was associated to the increase of autophagy, as revealed by the increase of the markers LC3B‐II and beclin I, detected by both immunofluorescence and western blot analysis. SI113 treatment caused also apoptosis of endometrial cancer cells, evidenced by the cleavage of the apoptotic markers PARP and Caspase‐9. Intriguingly, these effects were associated to the induction of endoplasmic reticulum stress markers GRP78 and CHOP evaluated by both Real‐Time RT‐PCR and Western Blot analysis. Increased expression of SGK1 in endometrial cancer tissues suggest a role for SGK1 in this type of cancer, as reported for other malignancies. Moreover, the efficacy of SI113 in affecting endometrial cancer cells viability, possibly via endoplasmic reticulum stress activation, identifies SGK1 as an attractive molecular target for new tailored therapeutic intervention for the treatment of endometrial cancer.
SGK1 expression is increased in endometrial cancer SI113, an inhibitor of SGK1, induces endoplasmic reticulum stress, autophagy, and apoptosis in endometrial cancer cells. |
| doi_str_mv | 10.1002/jcp.25850 |
| format | Article |
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SGK1 expression is increased in endometrial cancer SI113, an inhibitor of SGK1, induces endoplasmic reticulum stress, autophagy, and apoptosis in endometrial cancer cells.</description><identifier>ISSN: 0021-9541</identifier><identifier>EISSN: 1097-4652</identifier><identifier>DOI: 10.1002/jcp.25850</identifier><identifier>PMID: 28177128</identifier><language>eng</language><publisher>United States: Wiley Subscription Services, Inc</publisher><subject>1-Phosphatidylinositol 3-kinase ; AKT protein ; Antineoplastic Agents - pharmacology ; Apoptosis ; Apoptosis - drug effects ; Autophagy ; Autophagy - drug effects ; Beclin-1 - metabolism ; Cancer ; Case-Control Studies ; Caspase ; Caspase 9 - metabolism ; Caspase-9 ; Cell Line, Tumor ; Cell Survival - drug effects ; Deregulation ; Dose-Response Relationship, Drug ; Endometrial cancer ; Endometrial Neoplasms - drug therapy ; Endometrial Neoplasms - enzymology ; Endometrial Neoplasms - genetics ; Endometrial Neoplasms - pathology ; Endometrium ; Endoplasmic reticulum ; endoplasmic reticulum stress ; Endoplasmic Reticulum Stress - drug effects ; Female ; Heat-Shock Proteins - genetics ; Heat-Shock Proteins - metabolism ; Humans ; Immediate-Early Proteins - antagonists & inhibitors ; Immediate-Early Proteins - metabolism ; Immunofluorescence ; Inhibitors ; Kinases ; Markers ; Microtubule-Associated Proteins - metabolism ; Middle Aged ; Phagocytosis ; Poly(ADP-ribose) polymerase ; Poly(ADP-ribose) Polymerases - metabolism ; Polymerase chain reaction ; Protein kinase ; Protein Kinase Inhibitors - pharmacology ; Protein-Serine-Threonine Kinases - antagonists & inhibitors ; Protein-Serine-Threonine Kinases - metabolism ; Protein-serine/threonine kinase ; Pyrazoles - pharmacology ; Pyrimidines - pharmacology ; SGK1 ; Signal Transduction - drug effects ; Stresses ; Structure-function relationships ; Transcription Factor CHOP - genetics ; Transcription Factor CHOP - metabolism ; Tumors ; Viability</subject><ispartof>Journal of cellular physiology, 2017-12, Vol.232 (12), p.3735-3743</ispartof><rights>2017 Wiley Periodicals, Inc.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3530-547c49cc6d25a5d727c70d72a397eba339843e16e54d0c7388580866b6ede7323</citedby><cites>FETCH-LOGICAL-c3530-547c49cc6d25a5d727c70d72a397eba339843e16e54d0c7388580866b6ede7323</cites><orcidid>0000-0002-8496-3538</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fjcp.25850$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fjcp.25850$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28177128$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Conza, Domenico</creatorcontrib><creatorcontrib>Mirra, Paola</creatorcontrib><creatorcontrib>Calì, Gaetano</creatorcontrib><creatorcontrib>Tortora, Teresa</creatorcontrib><creatorcontrib>Insabato, Luigi</creatorcontrib><creatorcontrib>Fiory, Francesca</creatorcontrib><creatorcontrib>Schenone, Silvia</creatorcontrib><creatorcontrib>Amato, Rosario</creatorcontrib><creatorcontrib>Beguinot, Francesco</creatorcontrib><creatorcontrib>Perrotti, Nicola</creatorcontrib><creatorcontrib>Ulianich, Luca</creatorcontrib><title>The SGK1 inhibitor SI113 induces autophagy, apoptosis, and endoplasmic reticulum stress in endometrial cancer cells</title><title>Journal of cellular physiology</title><addtitle>J Cell Physiol</addtitle><description>Endometrial cancer is often characterized by PI3K/AKT pathway deregulation. Recently it has been suggested that SGK1, a serine/threonine protein kinase that shares structural and functional similarities with the AKT family, might play a role in cancer, since its expression and/or activity has been found to be deregulated in different human tumors. However, the role of SGK1 in endometrial cancer has been poorly investigated. Here, we show that SGK1 expression is increased in tissue specimens from neoplastic endometrium. The SGK1 inhibitor SI113 induced a significant reduction of endometrial cancer cells viability, measured by the (3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyl tetrazolium bromide assay. This effect was associated to the increase of autophagy, as revealed by the increase of the markers LC3B‐II and beclin I, detected by both immunofluorescence and western blot analysis. SI113 treatment caused also apoptosis of endometrial cancer cells, evidenced by the cleavage of the apoptotic markers PARP and Caspase‐9. Intriguingly, these effects were associated to the induction of endoplasmic reticulum stress markers GRP78 and CHOP evaluated by both Real‐Time RT‐PCR and Western Blot analysis. Increased expression of SGK1 in endometrial cancer tissues suggest a role for SGK1 in this type of cancer, as reported for other malignancies. Moreover, the efficacy of SI113 in affecting endometrial cancer cells viability, possibly via endoplasmic reticulum stress activation, identifies SGK1 as an attractive molecular target for new tailored therapeutic intervention for the treatment of endometrial cancer.
SGK1 expression is increased in endometrial cancer SI113, an inhibitor of SGK1, induces endoplasmic reticulum stress, autophagy, and apoptosis in endometrial cancer cells.</description><subject>1-Phosphatidylinositol 3-kinase</subject><subject>AKT protein</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Autophagy</subject><subject>Autophagy - drug effects</subject><subject>Beclin-1 - metabolism</subject><subject>Cancer</subject><subject>Case-Control Studies</subject><subject>Caspase</subject><subject>Caspase 9 - metabolism</subject><subject>Caspase-9</subject><subject>Cell Line, Tumor</subject><subject>Cell Survival - drug effects</subject><subject>Deregulation</subject><subject>Dose-Response Relationship, Drug</subject><subject>Endometrial cancer</subject><subject>Endometrial Neoplasms - drug therapy</subject><subject>Endometrial Neoplasms - enzymology</subject><subject>Endometrial Neoplasms - genetics</subject><subject>Endometrial Neoplasms - pathology</subject><subject>Endometrium</subject><subject>Endoplasmic reticulum</subject><subject>endoplasmic reticulum stress</subject><subject>Endoplasmic Reticulum Stress - drug effects</subject><subject>Female</subject><subject>Heat-Shock Proteins - genetics</subject><subject>Heat-Shock Proteins - metabolism</subject><subject>Humans</subject><subject>Immediate-Early Proteins - antagonists & inhibitors</subject><subject>Immediate-Early Proteins - metabolism</subject><subject>Immunofluorescence</subject><subject>Inhibitors</subject><subject>Kinases</subject><subject>Markers</subject><subject>Microtubule-Associated Proteins - metabolism</subject><subject>Middle Aged</subject><subject>Phagocytosis</subject><subject>Poly(ADP-ribose) polymerase</subject><subject>Poly(ADP-ribose) Polymerases - metabolism</subject><subject>Polymerase chain reaction</subject><subject>Protein kinase</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Protein-Serine-Threonine Kinases - antagonists & inhibitors</subject><subject>Protein-Serine-Threonine Kinases - metabolism</subject><subject>Protein-serine/threonine kinase</subject><subject>Pyrazoles - pharmacology</subject><subject>Pyrimidines - pharmacology</subject><subject>SGK1</subject><subject>Signal Transduction - drug effects</subject><subject>Stresses</subject><subject>Structure-function relationships</subject><subject>Transcription Factor CHOP - genetics</subject><subject>Transcription Factor CHOP - metabolism</subject><subject>Tumors</subject><subject>Viability</subject><issn>0021-9541</issn><issn>1097-4652</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kFFLwzAUhYMobk4f_AMS8EmwW9I0TfMoQ-d0oLD5XLL0zmW0TU1aZP_euKpvPp17Od89Fw5Cl5SMKSHxZKebccwzTo7QkBIpoiTl8TEaBo9Gkid0gM683xFCpGTsFA3ijApB42yI_GoLeDl7ptjUW7M2rXV4OaeUhb3oNHisutY2W_W-v8WqsU1rvfFhrAsMdWGbUvnKaOygNboruwr71oH34fzgV9A6o0qsVa3BYQ1l6c_RyUaVHi5-dITeHu5X08do8TKbT-8WkWackYgnQidS67SIueKFiIUWJIhiUsBaMSazhAFNgScF0YJlGc9IlqbrFAoQLGYjdN3nNs5-dODbfGc7V4eXOZWMSJoQzgN101PaWe8dbPLGmUq5fU5J_l1vHurND_UG9uonsVtXUPyRv30GYNIDn6aE_f9J-dP0tY_8Akftg1k</recordid><startdate>201712</startdate><enddate>201712</enddate><creator>Conza, Domenico</creator><creator>Mirra, Paola</creator><creator>Calì, Gaetano</creator><creator>Tortora, Teresa</creator><creator>Insabato, Luigi</creator><creator>Fiory, Francesca</creator><creator>Schenone, Silvia</creator><creator>Amato, Rosario</creator><creator>Beguinot, Francesco</creator><creator>Perrotti, Nicola</creator><creator>Ulianich, Luca</creator><general>Wiley Subscription Services, Inc</general><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>7TK</scope><scope>7U7</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>K9.</scope><scope>P64</scope><scope>RC3</scope><orcidid>https://orcid.org/0000-0002-8496-3538</orcidid></search><sort><creationdate>201712</creationdate><title>The SGK1 inhibitor SI113 induces autophagy, apoptosis, and endoplasmic reticulum stress in endometrial cancer cells</title><author>Conza, Domenico ; Mirra, Paola ; Calì, Gaetano ; Tortora, Teresa ; Insabato, Luigi ; Fiory, Francesca ; Schenone, Silvia ; Amato, Rosario ; Beguinot, Francesco ; Perrotti, Nicola ; Ulianich, Luca</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3530-547c49cc6d25a5d727c70d72a397eba339843e16e54d0c7388580866b6ede7323</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>1-Phosphatidylinositol 3-kinase</topic><topic>AKT protein</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Apoptosis</topic><topic>Apoptosis - drug effects</topic><topic>Autophagy</topic><topic>Autophagy - drug effects</topic><topic>Beclin-1 - metabolism</topic><topic>Cancer</topic><topic>Case-Control Studies</topic><topic>Caspase</topic><topic>Caspase 9 - metabolism</topic><topic>Caspase-9</topic><topic>Cell Line, Tumor</topic><topic>Cell Survival - drug effects</topic><topic>Deregulation</topic><topic>Dose-Response Relationship, Drug</topic><topic>Endometrial cancer</topic><topic>Endometrial Neoplasms - drug therapy</topic><topic>Endometrial Neoplasms - enzymology</topic><topic>Endometrial Neoplasms - genetics</topic><topic>Endometrial Neoplasms - pathology</topic><topic>Endometrium</topic><topic>Endoplasmic reticulum</topic><topic>endoplasmic reticulum stress</topic><topic>Endoplasmic Reticulum Stress - drug effects</topic><topic>Female</topic><topic>Heat-Shock Proteins - genetics</topic><topic>Heat-Shock Proteins - metabolism</topic><topic>Humans</topic><topic>Immediate-Early Proteins - antagonists & inhibitors</topic><topic>Immediate-Early Proteins - metabolism</topic><topic>Immunofluorescence</topic><topic>Inhibitors</topic><topic>Kinases</topic><topic>Markers</topic><topic>Microtubule-Associated Proteins - metabolism</topic><topic>Middle Aged</topic><topic>Phagocytosis</topic><topic>Poly(ADP-ribose) polymerase</topic><topic>Poly(ADP-ribose) Polymerases - metabolism</topic><topic>Polymerase chain reaction</topic><topic>Protein kinase</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Protein-Serine-Threonine Kinases - antagonists & inhibitors</topic><topic>Protein-Serine-Threonine Kinases - metabolism</topic><topic>Protein-serine/threonine kinase</topic><topic>Pyrazoles - pharmacology</topic><topic>Pyrimidines - pharmacology</topic><topic>SGK1</topic><topic>Signal Transduction - drug effects</topic><topic>Stresses</topic><topic>Structure-function relationships</topic><topic>Transcription Factor CHOP - genetics</topic><topic>Transcription Factor CHOP - metabolism</topic><topic>Tumors</topic><topic>Viability</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Conza, Domenico</creatorcontrib><creatorcontrib>Mirra, Paola</creatorcontrib><creatorcontrib>Calì, Gaetano</creatorcontrib><creatorcontrib>Tortora, Teresa</creatorcontrib><creatorcontrib>Insabato, Luigi</creatorcontrib><creatorcontrib>Fiory, Francesca</creatorcontrib><creatorcontrib>Schenone, Silvia</creatorcontrib><creatorcontrib>Amato, Rosario</creatorcontrib><creatorcontrib>Beguinot, Francesco</creatorcontrib><creatorcontrib>Perrotti, Nicola</creatorcontrib><creatorcontrib>Ulianich, Luca</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><jtitle>Journal of cellular physiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Conza, Domenico</au><au>Mirra, Paola</au><au>Calì, Gaetano</au><au>Tortora, Teresa</au><au>Insabato, Luigi</au><au>Fiory, Francesca</au><au>Schenone, Silvia</au><au>Amato, Rosario</au><au>Beguinot, Francesco</au><au>Perrotti, Nicola</au><au>Ulianich, Luca</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The SGK1 inhibitor SI113 induces autophagy, apoptosis, and endoplasmic reticulum stress in endometrial cancer cells</atitle><jtitle>Journal of cellular physiology</jtitle><addtitle>J Cell Physiol</addtitle><date>2017-12</date><risdate>2017</risdate><volume>232</volume><issue>12</issue><spage>3735</spage><epage>3743</epage><pages>3735-3743</pages><issn>0021-9541</issn><eissn>1097-4652</eissn><abstract>Endometrial cancer is often characterized by PI3K/AKT pathway deregulation. Recently it has been suggested that SGK1, a serine/threonine protein kinase that shares structural and functional similarities with the AKT family, might play a role in cancer, since its expression and/or activity has been found to be deregulated in different human tumors. However, the role of SGK1 in endometrial cancer has been poorly investigated. Here, we show that SGK1 expression is increased in tissue specimens from neoplastic endometrium. The SGK1 inhibitor SI113 induced a significant reduction of endometrial cancer cells viability, measured by the (3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyl tetrazolium bromide assay. This effect was associated to the increase of autophagy, as revealed by the increase of the markers LC3B‐II and beclin I, detected by both immunofluorescence and western blot analysis. SI113 treatment caused also apoptosis of endometrial cancer cells, evidenced by the cleavage of the apoptotic markers PARP and Caspase‐9. Intriguingly, these effects were associated to the induction of endoplasmic reticulum stress markers GRP78 and CHOP evaluated by both Real‐Time RT‐PCR and Western Blot analysis. Increased expression of SGK1 in endometrial cancer tissues suggest a role for SGK1 in this type of cancer, as reported for other malignancies. Moreover, the efficacy of SI113 in affecting endometrial cancer cells viability, possibly via endoplasmic reticulum stress activation, identifies SGK1 as an attractive molecular target for new tailored therapeutic intervention for the treatment of endometrial cancer.
SGK1 expression is increased in endometrial cancer SI113, an inhibitor of SGK1, induces endoplasmic reticulum stress, autophagy, and apoptosis in endometrial cancer cells.</abstract><cop>United States</cop><pub>Wiley Subscription Services, Inc</pub><pmid>28177128</pmid><doi>10.1002/jcp.25850</doi><tpages>9</tpages><orcidid>https://orcid.org/0000-0002-8496-3538</orcidid></addata></record> |
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| subjects | 1-Phosphatidylinositol 3-kinase AKT protein Antineoplastic Agents - pharmacology Apoptosis Apoptosis - drug effects Autophagy Autophagy - drug effects Beclin-1 - metabolism Cancer Case-Control Studies Caspase Caspase 9 - metabolism Caspase-9 Cell Line, Tumor Cell Survival - drug effects Deregulation Dose-Response Relationship, Drug Endometrial cancer Endometrial Neoplasms - drug therapy Endometrial Neoplasms - enzymology Endometrial Neoplasms - genetics Endometrial Neoplasms - pathology Endometrium Endoplasmic reticulum endoplasmic reticulum stress Endoplasmic Reticulum Stress - drug effects Female Heat-Shock Proteins - genetics Heat-Shock Proteins - metabolism Humans Immediate-Early Proteins - antagonists & inhibitors Immediate-Early Proteins - metabolism Immunofluorescence Inhibitors Kinases Markers Microtubule-Associated Proteins - metabolism Middle Aged Phagocytosis Poly(ADP-ribose) polymerase Poly(ADP-ribose) Polymerases - metabolism Polymerase chain reaction Protein kinase Protein Kinase Inhibitors - pharmacology Protein-Serine-Threonine Kinases - antagonists & inhibitors Protein-Serine-Threonine Kinases - metabolism Protein-serine/threonine kinase Pyrazoles - pharmacology Pyrimidines - pharmacology SGK1 Signal Transduction - drug effects Stresses Structure-function relationships Transcription Factor CHOP - genetics Transcription Factor CHOP - metabolism Tumors Viability |
| title | The SGK1 inhibitor SI113 induces autophagy, apoptosis, and endoplasmic reticulum stress in endometrial cancer cells |
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