Department of Biological and Environmental Science and Technologies (DiSTeBA), University of Salento, Via Prov. le Lecce-Monteroni, 73100 Lecce, Italy.
Department of Biological and Environmental Science and Technologies (DiSTeBA), University of Salento, Via Prov. le Lecce-Monteroni, 73100 Lecce, Italy.
Biochem Pharmacol. 2021 Oct;192:114702. doi: 10.1016/j.bcp.2021.114702. Epub 2021 Jul 26.
Platinum complexes are currently used for breast cancer therapy, but, as with other drug classes, a series of intrinsic and acquired resistance mechanisms hinder their efficacy. To better understand the mechanisms underlying platinum complexes resistance in breast cancer, we generated a [Pt(O,O'-acac)(γ-acac)(DMS)]-resistant MCF-7, denoted as [Pt(acac)]R. [Pt(O,O'-acac)(γ-acac)(DMS)] was chosen as previous works showed that it has distinct mechanisms of action from cisplatin, especially with regard to cellular targets. [Pt(acac)]R cells are characterized by increased proliferation rates and aggressiveness with higher PKC-δ, BCL-2, MMP-9 and EGFR protein expressions and also by increased expression of various genes covering cell cycle regulation, invasion, survival, and hormone receptors. These [Pt(acac)]R cells also displayed high levels of activated signaling kinases Src, AKT and ERK/2. [Pt(acac)]R cells incubated with [Pt(O,O'-acac)(γ-acac)(DMS)], showed a relevant EGFR activation due to PKC-δ and Src phosphorylation that provoked proliferation and survival through MERK1/2/ERK1/2 and PI3K/Akt pathways. In addition, EGFR shuttled from the plasma membrane to the nucleus maybe acting as co-transcriptional factor. The data suggest that growth and survival of resistant cells rely upon a remarkable increase in EGFR level which, in collaboration with an enhanced role of PKC-δ and Src kinases support [Pt(acac)]R cell. It could therefore be assumed that combination treatments targeting both EGFR and PKC-δ/Src can improve therapy for breast cancer patients.
铂类复合物目前被用于乳腺癌治疗，但与其他药物类别一样，一系列内在和获得性耐药机制阻碍了其疗效。为了更好地理解乳腺癌中铂类复合物耐药的机制，我们生成了一种[Pt(O,O'-acac)(γ-acac)(DMS)]耐药 MCF-7 细胞系，命名为[Pt(acac)]R。[Pt(O,O'-acac)(γ-acac)(DMS)]被选择，是因为先前的研究表明，它与顺铂具有不同的作用机制，特别是在细胞靶标方面。[Pt(acac)]R 细胞的特征是增殖率和侵袭性增加，PKC-δ、BCL-2、MMP-9 和 EGFR 蛋白表达增加，以及涵盖细胞周期调节、侵袭、存活和激素受体的各种基因表达增加。这些[Pt(acac)]R 细胞还显示出高水平的激活信号激酶Src、AKT 和 ERK/2。用[Pt(O,O'-acac)(γ-acac)(DMS)]孵育[Pt(acac)]R 细胞，由于 PKC-δ 和 Src 的磷酸化导致 EGFR 激活，从而通过 MERK1/2/ERK1/2 和 PI3K/Akt 途径引发增殖和存活。此外，EGFR 从质膜转位到核内，可能作为共转录因子发挥作用。数据表明，耐药细胞的生长和存活依赖于 EGFR 水平的显著增加，该水平与 PKC-δ 和 Src 激酶的增强作用协同支持[Pt(acac)]R 细胞。因此，可以假设针对 EGFR 和 PKC-δ/Src 的联合治疗可以改善乳腺癌患者的治疗效果。
