Acquired cisplatin resistance in human ovarian A2780 cancer cells correlates with shift in taurine homeostasis and ability to volume regulate

Abstract

Sørensen BH, Thorsteinsdottir UA, Lambert IH. Acquired cisplatin resistance in human ovarian A2780 cancer cells correlates with shift in taurine homeostasis and ability to volume regulate. Am J Physiol Cell Physiol 307: C1071-C1080, 2014. First published September 24, 2014; doi:10.1152/ajpcell.00274.2014.-Cisplatin resistance is a major challenge in the treatment of cancer and develops through reduced drug accumulation and an increased ability to avoid drug-induced cell damage, cell shrinkage, and hence initiation of apoptosis. Uptake and release of the semiessential amino acid taurine contribute to cell volume homeostasis, and taurine has been reported to have antiapoptotic effects. Here we find that volume-sensitive taurine release in cisplatin-sensitive [wild-type (WT)] human ovarian cancer A2780 cells is reduced in the presence of the phospholipase A2 inhibitor bromenol lactone, the 5-lipoxygenase (5-LO) inhibitor ETH 615-139, and the cysteine leukotriene receptor 1 (CysLT1) antagonist zafirlukast and impaired by the anion channel blocker DIDS (4,4=-diisothiocyanatostilbene-2,2=-disulfonate). Comparing WT and cisplatin-resistant (RES) A2780 cells we also find that evasion of cisplatin-induced cell death in RES A2780 cells correlates with an increased accumulation of taurine, due to an increased taurine uptake and a concomitant impairment of the volume-sensitive taurine release pathway, as well an inability to reduce cell volume after osmotic cell swelling. Downregulation of volume-sensitive taurine release in RES A2780 cells correlates with reduced expression of the leucine-rich repeat-containing protein 8A (LRRC8A). Furthermore, acute (18 h) exposure to cisplatin (5-10 M) increases taurine release and LRRC8A expression in WT A2780 cells whereas cisplatin has no effect on LRRC8A expression in RES A2780 cells. It is suggested that shift in LRRC8A activity can be used as biomarker for apoptotic progress and acquirement of drug resistance. key word: platinum drugs; drug resistance; cell volume regulation; LRRC8A; TauT OVARIAN CANCER IS A LEADING cause of death among gynecological cancer patients, and the 5-yr survival rate has been estimated to 30% (64). The main reasons for the failure in treatment outcome are that 70% of the patients have already reached advanced stages of cancer progression at the time of diagnosis, i.e., the cancer has already spread within the pelvis and abdomen (68) and that most ovarian cancer cells rapidly develop resistance or multidrug resistance (MDR) against the chemotherapy.Cisplatin and chemotherapeutic resistance. Cisplatin was the first member of a class of platinum-based anticancer drugs, which also includes carboplatin and oxaliplatin (7,25), and today cisplatin is frequently used in chemotherapeutic treatment of ovarian cancer, lung cancer, and lymphomas (60). Cisplatin is administered to cancer patients intravenously as a sterile saline solution. Once circulating in the bloodstream, cisplatin is taken up by the cells and accumulated in the cell nucleus, where it causes DNA l...

Roles of the MST1-JNK signaling pathway in apoptosis of colorectal cancer cells induced by Taurine

“…The anti-tumor mechanism of Tau is mainly related to Tau-induced apoptosis, synergism, and attenuation [9–13], via regulating the expression of key genes at both the transcriptional and translational levels. For example, Zhang et al showed that Tau prompted the transcription and translation of the PUMA gene in HT-29 colorectal cancer cells [10], and Sorensen et al indicated that Tau increases LRRC8A expression in wild-type A2780 cells [22]; however, the specific mechanisms underlying these effects have not been elucidated. In the present study, we investigated the impact of Tau on apoptosis in CRC cells by changing the expression of MST1 gene or inhibiting the JNK pathway, aiming to investigate the roles of the MST1-JNK signaling pathway in the Tau-induced apoptosis in CRC cells.…”

Role of volume-regulated and calcium-activated anion channels in cell volume homeostasis, cancer and drug resistance

“…10C) and an inability to volume regulate. 95 Furthermore, 18 hour cisplatin treatment results in a 2-2.25 fold increase in the LRRC8A protein content in the cisplatin-sensitive A2780 cells (Fig. 12C), whereas the protein expression in resistant cells was unaffected by (Fig.…”

“…Comparing (i) non-adherent cisplatin sensitive EATC with adherent, cisplatin resistant ELA, 93 (ii) A2780 WT with A2780 RES (Fig. 10F) 94,95 as well as (iii) colorectal cancer cell lines (LoVo, SW480, DLD1, HT-29, HCT116) with normal colonocytes 96 it appears that TauT expression is high in drug resistant cells compared to their drug-sensitive parental counterparts which support earlier findings in kidney cells that cisplatin resistance complies with high expression of functional TauT. 97 Furthermore, similar to findings in colorectal cancer by Yasunaga and Matsumuru 96 we see that TauT knockdown enhances drug sensitivity in cisplatinresistant ELA cells (Fig.…”

Cisplatin activates volume sensitive LRRC8 channel mediated currents in Xenopus oocytes

“…cisplatin). [9][10][11][12][13] Additionally, patients with a low LRRC8D gene expression in their ovarian cancers displayed reduced survival. 10 Similarly, LRRC8D expression was shown to be essential for the cytotoxic effect of the antibiotic blasticidin S.…”