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    • Tamoxifen is still the most frequently used

    2021-09-16

    Tamoxifen is still the most frequently used selective estrogen receptor mediator (SERM) in premenopausal women suffering from estrogen receptor positive (ER+) breast carcinomas [15]. Although this therapy has been proven very successful, about 20–30% of ER+ breast tumors will not respond, or acquire resistance towards tamoxifen [16]. The molecular mechanism is still not completely understood, but the contribution of membrane bound estrogen receptors namely GPER1 or ERα splice products such as ERα36 have been implemented in acquired tamoxifen resistance [17], [18], [19], [20]. Upon activation of such estrogen receptors, signaling pathways involving MAP-kinases or phosphoinositide 3-kinase (PI3K) are activated which causes the matrix metallo proteases-mediated release of membrane bound growth factors especially epidermal growth factor (EGF) [21] or insulin-like growth factor 1 (IGF-1) [20]. Reliable, predictive markers and therapy concepts for tamoxifen resistant ER+ breast carcinomas are still not available. We have recently shown that tamoxifen resistant ER+ breast cancer Obeticholic Acid derived from the MCF-7 cell line were more sensitive towards aldehyde stress than the parental cell line [22]. This was associated with a decreased content of antioxidative sulfhydryl groups such as glutathione and a significantly enhanced activation of the redox responsive p38-MAP-kinase and the NF-κB transcription factor. As this possibly represents a general weakness associated with tamoxifen resistance that can potentially be exploited for therapy, we here investigated the mechanism of aldehyde toxicity further with the focus on reactive oxygen species, kinase signaling and the role of the aldehyde defense enzyme glyoxalase I.
    Material and methods
    Results
    Discussion We have shown earlier that tamoxifen resistance in a cellular model was associated with increased vulnerability towards the dicarbonyls methylglyoxal and glyoxal [22]. TamR cells exhibited decreased resistance towards these molecules and increased sensitivity of MAP-kinase and NF-κB signaling. We here analyzed this effect further by focusing on the mechanism of dicarbonyl stress associated signaling and the function of glyoxalase I for dicarbonyl resistance. As TamR cells contained less sulfhydryl groups than the parental MCF-7 cell line, especially under dialdehyde stress, we suggested that this resulted in increased cell death caused by oxidative stress [22]. Free sulfhydryl groups are mainly provided by glutathione, which is also a cofactor for the glyoxalase reaction. In this viscous circle, dialdehyde stress can cause a ROS mediated depletion of glutathione, which is then no longer available for effective dicarbonyl detoxification, which in turn leads to more ROS production. Consistently, earlier reports have demonstrated that oxidative stress can inhibit aldehyde detoxification [32]. We show here that exogenous dicarbonyl stress indeed evoked oxidative stress in this mamma carcinoma cell line as determined by the H2DCFDA assay. Interestingly, the TamR-Md cell line showed an altered, more sensitive aldehyde dose response of ROS production than the parental MCF-7 cells. This is consistent with the postulated reduced antioxidative capacity. This was especially obvious for glyoxal, and this molecule also resulted in higher ROS amounts than methylglyoxal. This effect can in part be due to the presence of toxic formaldehyde in the methylglyoxal preparations that were used here. However, formaldehyde alone, in the concentrations present in the methylglyoxal, did not cause the effects on signaling described in this study (data not shown). The formation of dicarbonyl induced reactive oxygen species could be blocked by the NADPH-oxidase inhibitor DPI and cell survival could be improved by addition of the antioxidant NAC. Both observations support the hypothesis that dicarbonyl induced cell death was mediated by oxidative stress. This oxidative stress can in part be caused by the formation of advanced glycation end products (AGEs). AGEs activate the specific receptor RAGE (receptor for AGEs, or AGER1) which also causes increased formation of ROS via NADPH-oxidases [33], [34], [35] (for review see: [36]). As the formation of significant amounts of AGEs requires several hours, these molecules will not contribute to the early signaling responses, but can have effects at later time points. NAC can block oxidative stress for a sustained period of time and therefore resulted in increased survival of the cells.