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IL‐8 inhibits bortezomib‐induced apoptosis in ovarian cancer cells (1010.2)

Proteasome inhibition is a promising therapeutic strategy in a number of human cancers, including ovarian cancer, one of the most lethal human cancers. Bortezomib (BZ) is the first FDA approved proteasome inhibitor that has a remarkable anti‐tumor activity in many hematological malignancies. In solid tumors, BZ has been less effective; however, the underlying mechanisms are not fully understood. The rationale behind BZ development and use was its inhibition of NFκB activity and resulting suppression of NFκB‐dependent pro‐inflammatory and anti‐apoptotic genes. However, recent studies from our laboratory demonstrated that while BZ decreases expressions of most NFκB‐regulated genes, it actually increases expression of the pro‐inflammatory and pro‐angiogenic chemokine, IL‐8, in ovarian cancer cells. The goal of this study was to investigate whether the BZ‐increased IL‐8 expression regulates survival of ovarian cancer cells. Here, we show that suppression of IL‐8 levels by siRNA significantly induces apoptosis in BZ‐treated ovarian cancer SKOV3 cells. Our results indicate that the BZ‐increased IL‐8 expression represents one of the mechanisms responsible for the decreased BZ effectiveness in ovarian cancer, and suggest that a new combination therapy targeting the IL‐8 expression might enhance BZ effectiveness in ovarian cancer treatment.