Cancer cell sensitivity to bortezomib is associated with survivin and p53 status but not cancer cell types
Survivin is known playing a role in drug resistance. However, its role in bortezomib-mediated inhibition of growth and induction of apoptosis is unclear.
There are conflicting reports for the effect of bortezomib on survivin expression, which lacks of a plausible explanation.
Methods: In this study, we tested cancer cells with both p53 wild type and mutant/null background for the relationship of bortezomib resistance with survivin expression and p53 status using MTT assays, flow cytometry, western blots and siRNA technology.
Results: 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. Furthermore, silencing of survivin expression utilizing survivin mRNA-specific siRNA in p53 mutant or null cells sensitized cancer cells to bortezomib mediated apoptosis, suggesting a role for survivin in bortezomib resistance.
We further note 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, the effects of bortezomib on survivin expression appears to be dependent on the drug concentration and exposure time.
Conclusions: 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 likely impact the optimal clinical use of bortezomib in cancer therapeutics.
Author: Xiang LinfDiane CalinskiAsher Chanan-KhanMuxiang ZhouFengzhi Li
Credits/Source: Journal of Experimental &Clinical Cancer Research 2010, 29:8
Published on: 2010-01-22
Copyright by the authors listed above - made available via BioMedCentral (Open Access). Please
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