Cancer cell sensitivity to bortezomib is associated with survivin expression and p53 status but not cancer cell types

We found that cancer cells with wild type p53 show a low level expression of survivin and are sensitive to treatment with bortezomib, while cancer cells with a mutant or null p53 show a high level expression of survivin and are resistant to bortezomib-mediated apoptosis induction. However, silencing of survivin expression utilizing survivin mRNA-specific siRNA/shRNA in p53 mutant or null cells sensitized cancer cells to bortezomib mediated apoptosis induction, suggesting a role for survivin in bortezomib resistance. We further noted that modulation of survivin expression by bortezomib is dependent on p53 status but independent of cancer cell types. In cancer cells with mutated p53 or p53 null, bortezomib appears to induce survivin expression, while in cancer cells with wild type p53, bortezomib downregulates or shows no significant effect on survivin expression, which is dependent on the drug concentration, cell line and exposure time.Our findings, for the first time, unify the current inconsistent findings for bortezomib treatment and survivin expression, and linked the effect of bortezomib on survivin expression, apoptosis induction and bortezomib resistance in the relationship with p53 status, which is independent of cancer cell types. Further mechanistic studies along with this line may impact the optimal clinical application of bortezomib in solid cancer therapeutics.Although bortezomib (PS-341) was largely applied to treatment of hematopoietic malignancy such as myeloma, growing basic studies and clinical trials reveal that bortezomib can be used to treat many types of solid tumors alone and in combination with other chemotherapeutic drugs. This includes colon-gastric cancer [1-3], breast cancer [4-9], prostate cancer [10-14] and lung cancer [15-18] as well as others. Therefore, use of solid tumor-derived cancer cell lines to study the mechanism of bortezomib drug resistance is important for effective application of bortezomib in treatment of patients with sol