Journal
ONCOGENE
Volume 26, Issue 27, Pages 3972-3979Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.onc.1210166
Keywords
siRNA; off-target; seed; Mcl-1; ABT-737; Bcl-X-L
Ask authors/readers for more resources
ABT-737 is a subnanomolar inhibitor of the antiapoptotic proteins Bcl-2, Bcl-XL and Bcl-w. Although ABT-737 triggers extensive cell death in many small-cell lung carcinoma ( SCLC) cell lines, some of the SCLC cell lines and the majority of the cancer cell lines derived from other solid tumors were found to be resistant to ABT-737. To better understand the mechanism of resistance to ABT-737, we screened a short interfering RNA library consisting of short interfering RNA against 4000 'druggable' targets in an SCLC-derived cell line, NCI-H196. By comparing the knockdowns with phenotypes, all of the three top 'hits' from the screen were found to result from off-target gene silencing. Interestingly, the three off-target siRNAs were found to knock down an antiapoptotic Bcl-2 family protein Mcl-1 owing to the complementation between their seed regions with the 30 untranslated region ( 30 UTR) of Mcl-1. Furthermore, reducing the level of Mcl-1 using siRNAs or the small-molecule compounds Bay43-9006 and Seliciclib was sufficient to overcome the resistance to ABT-737 in the resistant SCLC cell line and cancer cell lines derived from other solid tumors. These results provide further evidence that Mcl-1 is the major factor that causes resistance to ABT-737 in cancer cells derived from diverse solid tumors, and the combination of Mcl-1 downregulating agents with ABT-737 could be potent therapeutic regimens for patient with ABT-737 resistant SCLC and many other types of solid tumors.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available