Medical School and State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China; State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Ministry of Science and Technology of China, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, China.
State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Ministry of Science and Technology of China, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, China.
Biochem Pharmacol. 2019 May;163:133-141. doi: 10.1016/j.bcp.2019.02.017. Epub 2019 Feb 14.
Palbociclib is a Cdk4/6 inhibitor approved for metastatic estrogen receptor-positive breast cancer. The drug is also under clinical evaluation for metastatic urothelial cancer and other solid tumors. Preclinical studies from multiple tumor types suggest that other factors also affect the sensitivity of individual tumors to Cdk4/6 inhibitor. We show here that Cdk2 has an essential role in palbociclib antitumor effect against bladder cancers. We found that palbociclib induced apoptosis instead of cell cycle arrest to exhibit its anticancer activity in T24 cells, as was evidenced by membrane blebbing, caspase-3 activation and AIF release from mitochondria. Cdk2 activation was important to palbociclib-induced apoptotic triggering activity, since depletion of Cdk2 significantly inhibited caspase-3 activation and cell apoptosis. Cdk2 activation caused p-Rad9 translocation to the mitochondria and subsequently interaction with Bcl-xl, leading to conformational activation of Bak and cell apoptosis. The anticancer activity and Cdk2 activation of palbociclib-treated mice were finally validated in a T24 xenograft model. Collectively, these results together demonstrate that palbociclib exerts its anticancer effect in T24 cells mainly through Cdk2 activation. Our findings provide new insights into the molecular interactions and anticancer mechanisms of Cdk4/6 inhibitors.
帕博西尼是一种 CDK4/6 抑制剂，已被批准用于转移性雌激素受体阳性乳腺癌。该药物也正在进行转移性尿路上皮癌和其他实体肿瘤的临床评估。来自多种肿瘤类型的临床前研究表明，其他因素也会影响个体肿瘤对 CDK4/6 抑制剂的敏感性。我们在这里表明 CDK2 在帕博西尼对膀胱癌的抗肿瘤作用中具有重要作用。我们发现，帕博西尼诱导细胞凋亡而不是细胞周期停滞来发挥其在 T24 细胞中的抗癌活性，这可以通过细胞膜起泡、caspase-3 激活和 AIF 从线粒体释放来证明。CDK2 激活对于帕博西尼诱导的凋亡触发活性很重要，因为 CDK2 的耗竭显著抑制了 caspase-3 的激活和细胞凋亡。CDK2 激活导致 p-Rad9 向线粒体易位，并随后与 Bcl-xl 相互作用，导致 Bak 的构象激活和细胞凋亡。最后，在 T24 异种移植模型中验证了帕博西尼治疗小鼠的抗癌活性和 CDK2 激活。总之，这些结果表明，帕博西尼在 T24 细胞中主要通过 CDK2 激活发挥其抗癌作用。我们的研究结果为 CDK4/6 抑制剂的分子相互作用和抗癌机制提供了新的见解。
