Constitutive BAK activation as a determinant of drug sensitivity in malignant lymphohematopoietic cells.
Mitochondrial outer membrane permeabilization (MOMP), a key step in the intrinsic apoptotic pathway, is incompletely understood. Current models emphasize the role of BH3-only BCL2 family members in BAX and BAK activation. Here we demonstrate concentration-dependent BAK autoactivation under cell-free conditions and provide evidence that this autoactivation plays a key role in regulating the intrinsic apoptotic pathway in intact cells. In particular, we show that up to 80% of BAK (but not BAX) in lymphohematopoietic cell lines is oligomerized and bound to anti-apoptotic BCL2 family members in the absence of exogenous death stimuli. The extent of this constitutive BAK oligomerization is diminished by BAK knockdown and unaffected by BIM or PUMA down-regulation. Further analysis indicates that sensitivity of cells to BH3 mimetics reflects the identity of the anti-apoptotic proteins to which BAK is constitutively bound, with extensive BCLXL•BAK complexes predicting navitoclax sensitivity, and extensive MCL1•BAK complexes predicting A1210477 sensitivity. Moreover, high BAK expression correlates with sensitivity of clinical acute myelogenous leukemia to chemotherapy, whereas low BAK levels correlate with resistance and relapse. Collectively, these results inform current understanding of MOMP and provide new insight into the ability of BH3 mimetics to induce apoptosis without directly activating BAX or BAK.
Division of Oncology Research, Mayo Clinic, Rochester, Minnesota 55905, USA; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota 55905, USA; Center for Medical Physics and Technology, Hefei Institutes of Physical Science, Chinese Academy of Science, Hefei 230031, China;
Haiming
H
Dai
Division of Oncology Research, Mayo Clinic, Rochester, Minnesota 55905, USA;
Husheng
H
Ding
Division of Oncology Research, Mayo Clinic, Rochester, Minnesota 55905, USA; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota 55905, USA;
X Wei
XW
Meng
Division of Oncology Research, Mayo Clinic, Rochester, Minnesota 55905, USA;
Kevin L
KL
Peterson
Division of Oncology Research, Mayo Clinic, Rochester, Minnesota 55905, USA;
Paula A
PA
Schneider
Sidney Kimmel Cancer Center at Johns Hopkins, Baltimore, Maryland 21287, USA.
Judith E
JE
Karp
Division of Oncology Research, Mayo Clinic, Rochester, Minnesota 55905, USA; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota 55905, USA;
Scott H
SH
Kaufmann
D000814:Aniline Compounds / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D019169:Jurkat Cells; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000503:physiopathology; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D015533:Transcriptional Activation / Q000235:genetics*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics* / Q000378:metabolism*; D051020:bcl-X Protein / Q000378:metabolism
D000814:Aniline Compounds; D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011994:Recombinant Proteins; D013449:Sulfonamides; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051020:bcl-X Protein; C528561:navitoclax
BAK; BH3 mimetic; apoptosis