BH3-only protein Bik is involved in both apoptosis induction and sensitivity to oxidative stress in multiple myeloma.
Bottom Line: Correlative study between Bik and thyrotroph embryonic factor (TEF) transcription factor expression was analysed by PCR.Stress oxidative response was analysed by flow cytometry. 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.
Affiliation: 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.Show MeSH
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Mentions: We used a fairly large number of HMCL (n=24) to analyse Bik expression. We found that only 9 HMCL (37.5%) displayed a moderate to strong expression of Bik protein. In contrast, weak expression or complete absence of Bik protein was observed in the other HMCL (Figure 1A). We also analysed Bik expression in CD138+ primary myeloma cells. Among 14 purified samples, Bik protein levels were moderate to high in eight, and low to absent in six primary myeloma samples. We, and others, have demonstrated that pairs like Mcl-1/Bim and Bcl-2/Bim may mutually regulate their expression (Jorgensen et al, 2007; Toumi-Wuillème et al, 2007). In view of these findings, we were interested to establish whether the absence or weak Bik expression detected in 62.5% of HMCL was related to the expression of Bcl-2 or Bcl-xL. Western blotting and further quantification analysis showed that Bik expression was directly correlated to Bcl-2 protein expression in both HMCL (Spearman's ρ=0.639 P=0.0006) (Figure 1C) and primary myeloma cells (Spearman's ρ=0.815 P=0.0005). However, no significant correlation was found between Bik and Bcl-xL expression (Spearman's ρ=0.079 P=0.711). Apart from Bik, we analysed the expression of other BH3-only proteins, as loss of Bik was previously shown to coincide with lack of Bim, Noxa and Bad in renal cell carcinoma (Sturm et al, 2006). Most HMCL expressed readily detectable levels of all three Bim isoforms EL, L and S (76%). Bad was constitutive and homogeneously expressed by all HMCL analysed (not shown). Despite of low or negative Noxa expression detected in around half of HMCL, no direct correlation with Bik expression was observed (Figure 1A). Altogether, these results suggest that in myeloma cells, Bik expression is directly correlated to Bcl-2 levels whereas there is no relationship between Bik expression and the expression of any other BH3-only protein studied.
Affiliation: 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.