The BH3 alpha-helical mimic BH3-M6 disrupts Bcl-X(L), Bcl-2, and MCL-1 protein-protein interactions with Bax, Bak, Bad, or Bim and induces apoptosis in a Bax- and Bim-dependent manner.
A critical hallmark of cancer cell survival is evasion of apoptosis. This is commonly due to overexpression of anti-apoptotic proteins such as Bcl-2, Bcl-X(L), and Mcl-1, which bind to the BH3 α-helical domain of pro-apoptotic proteins such as Bax, Bak, Bad, and Bim, and inhibit their function. We d...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
2011
|
| _version_ | 1826289076460847104 |
|---|---|
| author | Kazi, A Sun, J Doi, K Sung, S Takahashi, Y Yin, H Rodriguez, J Becerril, J Berndt, N Hamilton, A Wang, H Sebti, S |
| author_facet | Kazi, A Sun, J Doi, K Sung, S Takahashi, Y Yin, H Rodriguez, J Becerril, J Berndt, N Hamilton, A Wang, H Sebti, S |
| author_sort | Kazi, A |
| collection | OXFORD |
| description | A critical hallmark of cancer cell survival is evasion of apoptosis. This is commonly due to overexpression of anti-apoptotic proteins such as Bcl-2, Bcl-X(L), and Mcl-1, which bind to the BH3 α-helical domain of pro-apoptotic proteins such as Bax, Bak, Bad, and Bim, and inhibit their function. We designed a BH3 α-helical mimetic BH3-M6 that binds to Bcl-X(L) and Mcl-1 and prevents their binding to fluorescently labeled Bak- or Bim-BH3 peptides in vitro. Using several approaches, we demonstrate that BH3-M6 is a pan-Bcl-2 antagonist that inhibits the binding of Bcl-X(L), Bcl-2, and Mcl-1 to multi-domain Bax or Bak, or BH3-only Bim or Bad in cell-free systems and in intact human cancer cells, freeing up pro-apoptotic proteins to induce apoptosis. BH3-M6 disruption of these protein-protein interactions is associated with cytochrome c release from mitochondria, caspase-3 activation and PARP cleavage. Using caspase inhibitors and Bax and Bak siRNAs, we demonstrate that BH3-M6-induced apoptosis is caspase- and Bax-, but not Bak-dependent. Furthermore, BH3-M6 disrupts Bcl-X(L)/Bim, Bcl-2/Bim, and Mcl-1/Bim protein-protein interactions and frees up Bim to induce apoptosis in human cancer cells that depend for tumor survival on the neutralization of Bim with Bcl-X(L), Bcl-2, or Mcl-1. Finally, BH3-M6 sensitizes cells to apoptosis induced by the proteasome inhibitor CEP-1612. |
| first_indexed | 2024-03-07T02:23:23Z |
| format | Journal article |
| id | oxford-uuid:a4bbeec4-39ed-4e4c-b795-8690bfae56a1 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T02:23:23Z |
| publishDate | 2011 |
| record_format | dspace |
| spelling | oxford-uuid:a4bbeec4-39ed-4e4c-b795-8690bfae56a12022-03-27T02:35:48ZThe BH3 alpha-helical mimic BH3-M6 disrupts Bcl-X(L), Bcl-2, and MCL-1 protein-protein interactions with Bax, Bak, Bad, or Bim and induces apoptosis in a Bax- and Bim-dependent manner.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:a4bbeec4-39ed-4e4c-b795-8690bfae56a1EnglishSymplectic Elements at Oxford2011Kazi, ASun, JDoi, KSung, STakahashi, YYin, HRodriguez, JBecerril, JBerndt, NHamilton, AWang, HSebti, SA critical hallmark of cancer cell survival is evasion of apoptosis. This is commonly due to overexpression of anti-apoptotic proteins such as Bcl-2, Bcl-X(L), and Mcl-1, which bind to the BH3 α-helical domain of pro-apoptotic proteins such as Bax, Bak, Bad, and Bim, and inhibit their function. We designed a BH3 α-helical mimetic BH3-M6 that binds to Bcl-X(L) and Mcl-1 and prevents their binding to fluorescently labeled Bak- or Bim-BH3 peptides in vitro. Using several approaches, we demonstrate that BH3-M6 is a pan-Bcl-2 antagonist that inhibits the binding of Bcl-X(L), Bcl-2, and Mcl-1 to multi-domain Bax or Bak, or BH3-only Bim or Bad in cell-free systems and in intact human cancer cells, freeing up pro-apoptotic proteins to induce apoptosis. BH3-M6 disruption of these protein-protein interactions is associated with cytochrome c release from mitochondria, caspase-3 activation and PARP cleavage. Using caspase inhibitors and Bax and Bak siRNAs, we demonstrate that BH3-M6-induced apoptosis is caspase- and Bax-, but not Bak-dependent. Furthermore, BH3-M6 disrupts Bcl-X(L)/Bim, Bcl-2/Bim, and Mcl-1/Bim protein-protein interactions and frees up Bim to induce apoptosis in human cancer cells that depend for tumor survival on the neutralization of Bim with Bcl-X(L), Bcl-2, or Mcl-1. Finally, BH3-M6 sensitizes cells to apoptosis induced by the proteasome inhibitor CEP-1612. |
| spellingShingle | Kazi, A Sun, J Doi, K Sung, S Takahashi, Y Yin, H Rodriguez, J Becerril, J Berndt, N Hamilton, A Wang, H Sebti, S The BH3 alpha-helical mimic BH3-M6 disrupts Bcl-X(L), Bcl-2, and MCL-1 protein-protein interactions with Bax, Bak, Bad, or Bim and induces apoptosis in a Bax- and Bim-dependent manner. |
| title | The BH3 alpha-helical mimic BH3-M6 disrupts Bcl-X(L), Bcl-2, and MCL-1 protein-protein interactions with Bax, Bak, Bad, or Bim and induces apoptosis in a Bax- and Bim-dependent manner. |
| title_full | The BH3 alpha-helical mimic BH3-M6 disrupts Bcl-X(L), Bcl-2, and MCL-1 protein-protein interactions with Bax, Bak, Bad, or Bim and induces apoptosis in a Bax- and Bim-dependent manner. |
| title_fullStr | The BH3 alpha-helical mimic BH3-M6 disrupts Bcl-X(L), Bcl-2, and MCL-1 protein-protein interactions with Bax, Bak, Bad, or Bim and induces apoptosis in a Bax- and Bim-dependent manner. |
| title_full_unstemmed | The BH3 alpha-helical mimic BH3-M6 disrupts Bcl-X(L), Bcl-2, and MCL-1 protein-protein interactions with Bax, Bak, Bad, or Bim and induces apoptosis in a Bax- and Bim-dependent manner. |
| title_short | The BH3 alpha-helical mimic BH3-M6 disrupts Bcl-X(L), Bcl-2, and MCL-1 protein-protein interactions with Bax, Bak, Bad, or Bim and induces apoptosis in a Bax- and Bim-dependent manner. |
| title_sort | bh3 alpha helical mimic bh3 m6 disrupts bcl x l bcl 2 and mcl 1 protein protein interactions with bax bak bad or bim and induces apoptosis in a bax and bim dependent manner |
| work_keys_str_mv | AT kazia thebh3alphahelicalmimicbh3m6disruptsbclxlbcl2andmcl1proteinproteininteractionswithbaxbakbadorbimandinducesapoptosisinabaxandbimdependentmanner AT sunj thebh3alphahelicalmimicbh3m6disruptsbclxlbcl2andmcl1proteinproteininteractionswithbaxbakbadorbimandinducesapoptosisinabaxandbimdependentmanner AT doik thebh3alphahelicalmimicbh3m6disruptsbclxlbcl2andmcl1proteinproteininteractionswithbaxbakbadorbimandinducesapoptosisinabaxandbimdependentmanner AT sungs thebh3alphahelicalmimicbh3m6disruptsbclxlbcl2andmcl1proteinproteininteractionswithbaxbakbadorbimandinducesapoptosisinabaxandbimdependentmanner AT takahashiy thebh3alphahelicalmimicbh3m6disruptsbclxlbcl2andmcl1proteinproteininteractionswithbaxbakbadorbimandinducesapoptosisinabaxandbimdependentmanner AT yinh thebh3alphahelicalmimicbh3m6disruptsbclxlbcl2andmcl1proteinproteininteractionswithbaxbakbadorbimandinducesapoptosisinabaxandbimdependentmanner AT rodriguezj thebh3alphahelicalmimicbh3m6disruptsbclxlbcl2andmcl1proteinproteininteractionswithbaxbakbadorbimandinducesapoptosisinabaxandbimdependentmanner AT becerrilj thebh3alphahelicalmimicbh3m6disruptsbclxlbcl2andmcl1proteinproteininteractionswithbaxbakbadorbimandinducesapoptosisinabaxandbimdependentmanner AT berndtn thebh3alphahelicalmimicbh3m6disruptsbclxlbcl2andmcl1proteinproteininteractionswithbaxbakbadorbimandinducesapoptosisinabaxandbimdependentmanner AT hamiltona thebh3alphahelicalmimicbh3m6disruptsbclxlbcl2andmcl1proteinproteininteractionswithbaxbakbadorbimandinducesapoptosisinabaxandbimdependentmanner AT wangh thebh3alphahelicalmimicbh3m6disruptsbclxlbcl2andmcl1proteinproteininteractionswithbaxbakbadorbimandinducesapoptosisinabaxandbimdependentmanner AT sebtis thebh3alphahelicalmimicbh3m6disruptsbclxlbcl2andmcl1proteinproteininteractionswithbaxbakbadorbimandinducesapoptosisinabaxandbimdependentmanner AT kazia bh3alphahelicalmimicbh3m6disruptsbclxlbcl2andmcl1proteinproteininteractionswithbaxbakbadorbimandinducesapoptosisinabaxandbimdependentmanner AT sunj bh3alphahelicalmimicbh3m6disruptsbclxlbcl2andmcl1proteinproteininteractionswithbaxbakbadorbimandinducesapoptosisinabaxandbimdependentmanner AT doik bh3alphahelicalmimicbh3m6disruptsbclxlbcl2andmcl1proteinproteininteractionswithbaxbakbadorbimandinducesapoptosisinabaxandbimdependentmanner AT sungs bh3alphahelicalmimicbh3m6disruptsbclxlbcl2andmcl1proteinproteininteractionswithbaxbakbadorbimandinducesapoptosisinabaxandbimdependentmanner AT takahashiy bh3alphahelicalmimicbh3m6disruptsbclxlbcl2andmcl1proteinproteininteractionswithbaxbakbadorbimandinducesapoptosisinabaxandbimdependentmanner AT yinh bh3alphahelicalmimicbh3m6disruptsbclxlbcl2andmcl1proteinproteininteractionswithbaxbakbadorbimandinducesapoptosisinabaxandbimdependentmanner AT rodriguezj bh3alphahelicalmimicbh3m6disruptsbclxlbcl2andmcl1proteinproteininteractionswithbaxbakbadorbimandinducesapoptosisinabaxandbimdependentmanner AT becerrilj bh3alphahelicalmimicbh3m6disruptsbclxlbcl2andmcl1proteinproteininteractionswithbaxbakbadorbimandinducesapoptosisinabaxandbimdependentmanner AT berndtn bh3alphahelicalmimicbh3m6disruptsbclxlbcl2andmcl1proteinproteininteractionswithbaxbakbadorbimandinducesapoptosisinabaxandbimdependentmanner AT hamiltona bh3alphahelicalmimicbh3m6disruptsbclxlbcl2andmcl1proteinproteininteractionswithbaxbakbadorbimandinducesapoptosisinabaxandbimdependentmanner AT wangh bh3alphahelicalmimicbh3m6disruptsbclxlbcl2andmcl1proteinproteininteractionswithbaxbakbadorbimandinducesapoptosisinabaxandbimdependentmanner AT sebtis bh3alphahelicalmimicbh3m6disruptsbclxlbcl2andmcl1proteinproteininteractionswithbaxbakbadorbimandinducesapoptosisinabaxandbimdependentmanner |