Gamma-secretase inhibition attenuates oxaliplatin-induced apoptosis through increased Mcl-1 and/or Bcl-xL in human colon cancer cells
The Notch signaling pathway plays a significant role in differentiation, proliferation, apoptosis, and stem cell processes. It is essential for maintenance of the normal colon crypt and has been implicated in colorectal cancer oncogenesis. Downregulation of the Notch pathway through gamma-secretase...
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| Veröffentlicht in: | Apoptosis (London) 2013-10, Vol.18 (10), p.1163-1174 |
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| creator | Timme, Cindy R. Gruidl, Mike Yeatman, Timothy J. |
| description | The Notch signaling pathway plays a significant role in differentiation, proliferation, apoptosis, and stem cell processes. It is essential for maintenance of the normal colon crypt and has been implicated in colorectal cancer oncogenesis. Downregulation of the Notch pathway through gamma-secretase inhibitors (GSIs) has been shown to induce apoptosis and enhance response to chemotherapy in a variety of malignancies. In this study, we analyzed the effect of MRK-003 (Merck), a potent inhibitor of gamma-secretase, on oxaliplatin-induced apoptosis in colon cancer. Unexpectedly, gamma-secretase inhibition reduced oxaliplatin-induced apoptosis while GSI treatment alone was shown to have no effect on growth or apoptosis. We determined that the underlying mechanism of action involved an increase in protein levels of the anti-apoptotic Bcl-2 family members Mcl-1 and/or Bcl-xL which resulted in reduced Bax and Bak activation. Blocking of Mcl-1 and/or Bcl-xL through siRNA or the small molecule inhibitor obatoclax restored the apoptotic potential of cells treated with both oxaliplatin and MRK-003. Moreover, obatoclax synergized with MRK-003 alone to induce apoptosis. Our findings warrant caution when treating colon cancer with the combination of GSIs and chemotherapy, whereas other drug combinations, such as GSIs plus obatoclax, should be explored. |
| doi_str_mv | 10.1007/s10495-013-0883-x |
| format | Article |
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Moreover, obatoclax synergized with MRK-003 alone to induce apoptosis. Our findings warrant caution when treating colon cancer with the combination of GSIs and chemotherapy, whereas other drug combinations, such as GSIs plus obatoclax, should be explored.</description><identifier>ISSN: 1360-8185</identifier><identifier>EISSN: 1573-675X</identifier><identifier>DOI: 10.1007/s10495-013-0883-x</identifier><identifier>PMID: 23887890</identifier><language>eng</language><publisher>Boston: Springer US</publisher><subject>Adenocarcinoma - enzymology ; Adenocarcinoma - pathology ; Amyloid Precursor Protein Secretases - antagonists & inhibitors ; Antineoplastic Agents - pharmacology ; Apoptosis - drug effects ; bcl-X Protein - antagonists & inhibitors ; bcl-X Protein - genetics ; bcl-X Protein - metabolism ; Biochemistry ; Biomedical and Life Sciences ; Biomedicine ; Cancer Research ; Cell Biology ; Cell Line, Tumor ; Chemotherapy ; Colonic Neoplasms - enzymology ; Colonic Neoplasms - pathology ; Colorectal carcinoma ; Cyclic S-Oxides - pharmacology ; Drug Synergism ; Humans ; Myeloid Cell Leukemia Sequence 1 Protein - antagonists & inhibitors ; Myeloid Cell Leukemia Sequence 1 Protein - genetics ; Myeloid Cell Leukemia Sequence 1 Protein - metabolism ; Oncology ; Organoplatinum Compounds - pharmacology ; Original Paper ; Pyrroles - pharmacology ; RNA, Small Interfering - genetics ; Signal Transduction - drug effects ; Stem cells ; Thiadiazoles - pharmacology ; Virology</subject><ispartof>Apoptosis (London), 2013-10, Vol.18 (10), p.1163-1174</ispartof><rights>Springer Science+Business Media New York 2013</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c372t-f3651c9e29ebfc2baa2e3f6504276f7f864f643c6d39a98d1916c7bf69e6fb753</citedby><cites>FETCH-LOGICAL-c372t-f3651c9e29ebfc2baa2e3f6504276f7f864f643c6d39a98d1916c7bf69e6fb753</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s10495-013-0883-x$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s10495-013-0883-x$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27903,27904,41467,42536,51297</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23887890$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Timme, Cindy R.</creatorcontrib><creatorcontrib>Gruidl, Mike</creatorcontrib><creatorcontrib>Yeatman, Timothy J.</creatorcontrib><title>Gamma-secretase inhibition attenuates oxaliplatin-induced apoptosis through increased Mcl-1 and/or Bcl-xL in human colon cancer cells</title><title>Apoptosis (London)</title><addtitle>Apoptosis</addtitle><addtitle>Apoptosis</addtitle><description>The Notch signaling pathway plays a significant role in differentiation, proliferation, apoptosis, and stem cell processes. It is essential for maintenance of the normal colon crypt and has been implicated in colorectal cancer oncogenesis. Downregulation of the Notch pathway through gamma-secretase inhibitors (GSIs) has been shown to induce apoptosis and enhance response to chemotherapy in a variety of malignancies. In this study, we analyzed the effect of MRK-003 (Merck), a potent inhibitor of gamma-secretase, on oxaliplatin-induced apoptosis in colon cancer. Unexpectedly, gamma-secretase inhibition reduced oxaliplatin-induced apoptosis while GSI treatment alone was shown to have no effect on growth or apoptosis. We determined that the underlying mechanism of action involved an increase in protein levels of the anti-apoptotic Bcl-2 family members Mcl-1 and/or Bcl-xL which resulted in reduced Bax and Bak activation. Blocking of Mcl-1 and/or Bcl-xL through siRNA or the small molecule inhibitor obatoclax restored the apoptotic potential of cells treated with both oxaliplatin and MRK-003. Moreover, obatoclax synergized with MRK-003 alone to induce apoptosis. Our findings warrant caution when treating colon cancer with the combination of GSIs and chemotherapy, whereas other drug combinations, such as GSIs plus obatoclax, should be explored.</description><subject>Adenocarcinoma - enzymology</subject><subject>Adenocarcinoma - pathology</subject><subject>Amyloid Precursor Protein Secretases - antagonists & inhibitors</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Apoptosis - drug effects</subject><subject>bcl-X Protein - antagonists & inhibitors</subject><subject>bcl-X Protein - genetics</subject><subject>bcl-X Protein - metabolism</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Cancer Research</subject><subject>Cell Biology</subject><subject>Cell Line, Tumor</subject><subject>Chemotherapy</subject><subject>Colonic Neoplasms - enzymology</subject><subject>Colonic Neoplasms - pathology</subject><subject>Colorectal carcinoma</subject><subject>Cyclic S-Oxides - 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Academic</collection><jtitle>Apoptosis (London)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Timme, Cindy R.</au><au>Gruidl, Mike</au><au>Yeatman, Timothy J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Gamma-secretase inhibition attenuates oxaliplatin-induced apoptosis through increased Mcl-1 and/or Bcl-xL in human colon cancer cells</atitle><jtitle>Apoptosis (London)</jtitle><stitle>Apoptosis</stitle><addtitle>Apoptosis</addtitle><date>2013-10-01</date><risdate>2013</risdate><volume>18</volume><issue>10</issue><spage>1163</spage><epage>1174</epage><pages>1163-1174</pages><issn>1360-8185</issn><eissn>1573-675X</eissn><abstract>The Notch signaling pathway plays a significant role in differentiation, proliferation, apoptosis, and stem cell processes. It is essential for maintenance of the normal colon crypt and has been implicated in colorectal cancer oncogenesis. Downregulation of the Notch pathway through gamma-secretase inhibitors (GSIs) has been shown to induce apoptosis and enhance response to chemotherapy in a variety of malignancies. In this study, we analyzed the effect of MRK-003 (Merck), a potent inhibitor of gamma-secretase, on oxaliplatin-induced apoptosis in colon cancer. Unexpectedly, gamma-secretase inhibition reduced oxaliplatin-induced apoptosis while GSI treatment alone was shown to have no effect on growth or apoptosis. We determined that the underlying mechanism of action involved an increase in protein levels of the anti-apoptotic Bcl-2 family members Mcl-1 and/or Bcl-xL which resulted in reduced Bax and Bak activation. Blocking of Mcl-1 and/or Bcl-xL through siRNA or the small molecule inhibitor obatoclax restored the apoptotic potential of cells treated with both oxaliplatin and MRK-003. Moreover, obatoclax synergized with MRK-003 alone to induce apoptosis. Our findings warrant caution when treating colon cancer with the combination of GSIs and chemotherapy, whereas other drug combinations, such as GSIs plus obatoclax, should be explored.</abstract><cop>Boston</cop><pub>Springer US</pub><pmid>23887890</pmid><doi>10.1007/s10495-013-0883-x</doi><tpages>12</tpages></addata></record> |
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| subjects | Adenocarcinoma - enzymology Adenocarcinoma - pathology Amyloid Precursor Protein Secretases - antagonists & inhibitors Antineoplastic Agents - pharmacology Apoptosis - drug effects bcl-X Protein - antagonists & inhibitors bcl-X Protein - genetics bcl-X Protein - metabolism Biochemistry Biomedical and Life Sciences Biomedicine Cancer Research Cell Biology Cell Line, Tumor Chemotherapy Colonic Neoplasms - enzymology Colonic Neoplasms - pathology Colorectal carcinoma Cyclic S-Oxides - pharmacology Drug Synergism Humans Myeloid Cell Leukemia Sequence 1 Protein - antagonists & inhibitors Myeloid Cell Leukemia Sequence 1 Protein - genetics Myeloid Cell Leukemia Sequence 1 Protein - metabolism Oncology Organoplatinum Compounds - pharmacology Original Paper Pyrroles - pharmacology RNA, Small Interfering - genetics Signal Transduction - drug effects Stem cells Thiadiazoles - pharmacology Virology |
| title | Gamma-secretase inhibition attenuates oxaliplatin-induced apoptosis through increased Mcl-1 and/or Bcl-xL in human colon cancer cells |
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