Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA; Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA.
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Cell Chem Biol. 2017 Feb 16;24(2):218-230. doi: 10.1016/j.chembiol.2016.12.016. Epub 2017 Jan 26.
The proteasome inhibitors carfilzomib (Cfz) and bortezomib (Btz) are used successfully to treat multiple myeloma, but have not shown clinical efficacy in solid tumors. Here we show that clinically achievable inhibition of the β5 site of the proteasome by Cfz and Btz does not result in loss of viability of triple-negative breast cancer cell lines. We use site-specific inhibitors and CRISPR-mediated genetic inactivation of β1 and β2 to demonstrate that inhibiting a second site of the proteasome, particularly the β2 site, sensitizes cell lines to Btz and Cfz in vitro and in vivo. Inhibiting both β5 and β2 suppresses production of the soluble, active form of the transcription factor Nrf1 and prevents the recovery of proteasome activity through induction of new proteasomes. These findings provide a strong rationale for the development of dual β5 and β2 inhibitors for the treatment of solid tumors.
蛋白酶体抑制剂卡非佐米（Cfz）和硼替佐米（Btz）成功用于治疗多发性骨髓瘤，但在实体瘤中未显示出临床疗效。在这里，我们表明，通过 Cfz 和 Btz 对蛋白酶体β5 位点的临床可达到的抑制作用不会导致三阴性乳腺癌细胞系丧失活力。我们使用特异性抑制剂和 CRISPR 介导的β1 和β2 的基因失活来证明抑制蛋白酶体的第二个位点，特别是β2 位点，可使细胞系在体外和体内对 Btz 和 Cfz 敏感。抑制β5 和β2 均可抑制转录因子 Nrf1 的可溶性、活性形式的产生，并通过诱导新的蛋白酶体防止蛋白酶体活性的恢复。这些发现为开发用于治疗实体瘤的双重β5 和β2 抑制剂提供了强有力的依据。
