Annexin A4 induces platinum resistance in a chloride-and calcium-dependent manner

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.

High expression of XPA confers poor prognosis for nasopharyngeal carcinoma patients treated with platinum-based chemoradiotherapy

“…Although platinum has a miraculous initial therapeutic effect, unfortunately, it often leads to treatment failure because of intrinsic and extrinsic resistance to this drug. The potential mechanisms of platinum resistance [ 23 ] include reduced intracellular accumulation [ 24 , 25 ] and increased detoxification of cisplatin [ 26 ], increased capacity of DNA damage repair [ 7 , 9 ], inactivation of the apoptotic pathways [ 27 ] and other epigenetic alterations at molecular and cellular levels [ 28 , 29 ]. Among of them, increased capacity of DNA damage repair, especially the nucleotide excision repair (NER), is proposed to be one of the most crucial determinants [ 9 ].…”

New mechanisms for old drugs: Insights into DNA-unrelated effects of platinum compounds and drug resistance determinants

“…The release of Ca 2+ from ER stores causes activation of Ca 2+ -dependent calpains favoring Bid cleavage, an event occurring early in cisplatin-induced apoptosis (Mandic et al, 2002). Enhanced expression of the Ca 2+ -regulated phospholipid-binding protein Annexin 4 has been demonstrated to be critical for ovarian carcinoma cell resistance to cisplatin and carboplatin (Morimoto et al, 2014).…”

Potential targets for ovarian clear cell carcinoma: a review of updates and future perspectives

“…Increased expression of ABCC3 may, at least in part, be associated with the chemoresistant phenotype of CCC [ 19 ]. Moreover, AnxA4 overexpression reportedly stimulates efflux of platinum drugs and induces platinum resistance [ 20 , 54 , 55 ]. Increased sequestration of platinum agents in CCC has also been reported, with significantly increased glutathione concentrations in cell lines after cisplatin exposure [ 56 ].…”

“…Several studies have shown that AnxA4 induces drug resistance [ 20 ], and suppression of AnxA4 expression improved platinum sensitivity of CCC in vitro and in vivo [ 55 ]. In addition, Morimoto et al showed that annexin repeat domains and calcium-binding sites of repeated annexin sequences are required for resistance to platinum-based drugs [ 55 ]. The structure of AnxA4 and the mechanism of platinum resistance induced by AnxA4 is shown in Fig.…”