Influence of Bcl-2 Family Members on the Cellular Response of Small-Cell Lung Cancer Cell Lines to ABT-737

Tahir, Stephen K.; Yang, Xiufen; Anderson, Mark G.; Morgan-Lappe, Susan E.; Sarthy, Aparna V.; Chen, Jun; Warner, Robert B.; Ng, Shi-Chung; Fesik, Stephen W.; Elmore, Steve W.; Rosenberg, Saul H.; Tse, Christin

doi:10.1158/0008-5472.can-06-2203

Cited by 281 publications

(290 citation statements)

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“…Expression of Bcl-2 family members previously determined to influence sensitivity to ABT-737 was assessed in this panel of cell lines. Surprisingly, Mcl-1 levels, strongly implicated in sensitivity of SCLC to the drug (19,20,25), were remarkably constant in all cell lines tested, except for an ∼50% lower amount in the H146 cell line. This finding was even more surprising given the fact that Noxa levels varied by ∼10-fold in these cell lines and Noxa has been shown to regulate proteasomal degradation of Mcl-1 (23,28,29).…”

Section: Resultsmentioning

confidence: 89%

“…As would be expected, cell lines with low Mcl-1 tend to be more sensitive to the drug and knockdown of Mcl-1 enhances sensitivity. However, it is also clear that even in the initial study correlating SCLC sensitivity with Bcl-2 family expression (19), there was a wider range of variation in expression of other family members that correlated with sensitivity, such as Bcl-2 and Noxa, than there was in Mcl-1. When we assessed Bcl-2 family expression in a panel of SCLC cell lines with more than a 2-log difference in sensitivity to ABT-737, we were quite surprised to observe similar levels of Mcl-1 expression across the range (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Initial attention has focused heavily on the level of Mcl-1 expression as a rational explanation for variable sensitivity to ABT-737 based in part on the observation that it is the one prosurvival Bcl-2 family member present in SCLC that binds the drug poorly (19,20). As would be expected, cell lines with low Mcl-1 tend to be more sensitive to the drug and knockdown of Mcl-1 enhances sensitivity.…”

Section: Discussionmentioning

confidence: 99%

“…It is very effective in augmenting apoptosis in many cases, but SCLC is one of the few tumor types in which it induces apoptosis without an exogenous apoptotic stimulus. However, there is considerable variation in the sensitivities of different SCLC cell lines to this drug (18,19). Studies in a variety of cell types have suggested that indicators of sensitivity include low levels of Mcl-1 and high levels of Bcl-2, Bcl-X L , Bim, and Noxa expression (19)(20)(21)(22)(23)(24)(25).…”

Section: Introductionmentioning

confidence: 99%

“…However, there is considerable variation in the sensitivities of different SCLC cell lines to this drug (18,19). Studies in a variety of cell types have suggested that indicators of sensitivity include low levels of Mcl-1 and high levels of Bcl-2, Bcl-X L , Bim, and Noxa expression (19)(20)(21)(22)(23)(24)(25). In particular, studies in SCLC have documented that decreased Mcl-1 expression (19,20) and amplification of a region of chromosome 18 containing both the BCL-2 and NOXA genes correlates with increased sensitivity to ABT-737 (24).…”

Section: Introductionmentioning

confidence: 99%

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Alterations in the Noxa/Mcl-1 axis determine sensitivity of small cell lung cancer to the BH3 mimetic ABT-737

Hauck

Chao

Litz

et al. 2009

Molecular Cancer Therapeutics

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To understand the molecular basis for variable sensitivity to the BH3 mimetic drug ABT-737, the abundance of Bcl-2 family members was assayed in a panel of small cell lung cancer cell lines whose sensitivity varied over a 2-log range. Elevated Noxa and Bcl-2 levels directly correlated with sensitivity to ABT-737, whereas Mcl-1 levels were similar in all cell lines tested regardless of sensitivity. Transgenically enforced expression of Noxa but not Bcl-2 resulted in increased sensitivity to ABT-737 in multiple cell lines. This increase was especially pronounced in the H209 cell line in which expression of Noxa resulted in a proportionate decline in Mcl-1 expression. Although overexpression of Noxa enhanced sensitivity of the H526 and H82 cell lines to ABT-737, it did not result in altered Mcl-1 levels. Similarly, small interfering RNA-mediated knockdown of Noxa expression in the H146 cell line, which increased resistance to ABT-737, did not result in altered Mcl-1 levels. Therefore, three of four cell lines studied failed to show Noxa-mediated regulation of Mcl-1 expression. However, despite failure to regulate Mcl-1 levels, Noxa blocked binding of Bim to Mcl-1 following its release from Bcl-2 by ABT-737. Finally, we observed that a 24-hour incubation of the H526 and WBA cell lines with ABT-737 resulted in increased Noxa expression, suggesting that Noxa may play a direct role in ABT-737-mediated apoptosis. These results indicate that Noxa expression is the critical determinant of ABT-737 sensitivity and loss of Noxa-mediated regulation of Mcl-1 expression may be an important feature of small cell lung cancer biology. [Mol Cancer Ther 2009;8(4):883-92]

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