BH3-only protein Bik is involved in both apoptosis induction and sensitivity to oxidative stress in multiple myeloma.
BACKGROUND
although gene expression profile of multiple myeloma (MM) patients shows a wide range of Bik/Nbk expression, varying from absent to high, its regulation and function in myeloma cells is poorly understood. Thus, we addressed these questions in MM.


METHODS
human myeloma cell lines (HMCLs) and primary purified myeloma cells were studied for Bcl-2 family protein expression by western blot and further correlation analysis was performed. Correlative study between Bik and thyrotroph embryonic factor (TEF) transcription factor expression was analysed by PCR. Stress oxidative response was analysed by flow cytometry.


RESULTS
a strong expression of Bik protein was found only in one out of three of HMCL and correlated to Bcl-2 expression (P=0.0006). We demonstrated that Bik could be regulated at the protein level by Bcl-2 and at the transcriptional level by TEF. Bik overexpression sensitises myeloma cells to oxidative stress whereas Bik silencing increases resistance to H(2)O(2) oxidative stress. Furthermore, Bik ectopic expression disrupts Bim/Bcl-2 and Bim/Bcl-xL endogenous complexes triggering Bim release that could induce Bax and Bak activation.


CONCLUSIONS
ours results suggest that Bik has a role in both, apoptosis induction and sensitivity to oxidative stress in myeloma cells. Small BH3 mimetic molecules should be considered for further apoptosis-based therapy in myeloma cells expressing endogenous Bik/Bcl-2 complexes.
Institut de Recherche Thérapeutique de l'Université de Nantes, Equipe 10 labellisée Ligue Nationale contre le Cancer 2008, 8 quai Moncousu, Nantes BP70721 F-44007, France.
L
L
Bodet
E
E
Ménoret
G
G
Descamps
C
C
Pellat-Deceunynck
R
R
Bataille
S
S
Le Gouill
P
P
Moreau
M
M
Amiot
P
P
Gomez-Bougie
D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000502:physiology*; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D024101:Mitochondrial Proteins; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology*; D018384:Oxidative Stress; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D012333:RNA, Messenger / Q000032:analysis; D016159:Tumor Suppressor Protein p53 / Q000032:analysis
D051017:Apoptosis Regulatory Proteins; C096820:BIK protein, human; D050976:Basic-Leucine Zipper Transcription Factors; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; C489490:TEF protein, human; D016159:Tumor Suppressor Protein p53