Abstract
Platinum resistance has long been a major issue in the treatment of various cancers. We previously reported that enhanced annexin A4 (ANXA4) expression, a Ca2+-regulated phospholipid-binding protein, induces chemoresistance to platinum-based drugs. In this study, we investigated the role of annexin repeats, a conserved structure of all the annexin family, responsible for platinum-resistance as well as the effect of knockdown of ANXA4. ANXA4 knockdown increased sensitivity to platinum-based drugs both in vitro and in vivo. To identify the domain responsible for chemoresistance, ANXA4 deletion mutants were constructed by deleting annexin repeats one by one from the C terminus. Platinum resistance was induced both in vitro and in vivo in cells expressing either full-length ANXA4 or the deletion mutants, containing at least one intact annexin repeat. However, cells expressing the mutant without any calcium-binding sites in the annexin repeated sequence, which is essential for ANXA4 translocation from the cytosol to plasma membrane, failed to acquire platinum resistance. After cisplatin treatment, the intracellular chloride ion concentration, whose channel is partly regulated by ANXA4, significantly increased in the platinum-resistant cells. These findings indicate that the calcium-binding site in the annexin repeat induces chemoresistance to the platinum-based drug by elevating the intracellular chloride concentration.
Highlights
Since cisplatin was first introduced as an anticancer drug in the 1970s [1], various platinum-based drugs have been developed and widely used against gynecological and against other cancers, including lung, colorectal, testicular, prostate and bladder cancer [26]
The factors associated with annexin A4 (ANXA4)-induced chemoresistance have been reported, such as NF-κB [45] and ATP7A [44], but the structure of the protein, i.e. annexin repeats and calcium-binding sites in the annexin repeated sequence, has not been taken into account in relation to the ANXA4-induced chemoresistance
We showed that ANXA4 knockdown improved sensitivity to platinum drugs, and annexin repeats were involved in chemoresistance
Summary
Since cisplatin was first introduced as an anticancer drug in the 1970s [1], various platinum-based drugs have been developed and widely used against gynecological and against other cancers, including lung, colorectal, testicular, prostate and bladder cancer [26]. The annexin repeat possesses the calcium and membrane binding sites and is responsible for mediating the canonical membrane binding properties [29] These domains in ANXA4 are surrounded by relatively short amino and carboxy termini that do not have any known function [30]. ANXA4 has been shown to be associated with resistance to platinum-based drugs [28, 41,42,43]
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