Palbociclib Renders Human Papilloma Virus-Negative Head and Neck Squamous Cell Carcinoma Vulnerable to the Senolytic Agent Navitoclax.
Palbociclib Renders Human Papilloma Virus-Negative Head and Neck Squamous Cell Carcinoma Vulnerable to the Senolytic Agent Navitoclax.
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DOI：
10.1158/1541-7786.mcr-20-0915
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发表时间：
2021-05
期刊：
影响因子：
--
通讯作者：
Ow TJ
中科院分区：
文献类型：
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作者：
Gadsden NJ;Fulcher CD;Li D;Shrivastava N;Thomas C;Segall JE;Prystowsky MB;Schlecht NF;Gavathiotis E;Ow TJ
我们证明，细胞周期蛋白依赖性激酶4/6（CDK 4/6）的抑制导致衰老的人乳头瘤病毒（HPV）阴性（−）的头颈部鳞状细胞癌（HNSCC），但不是在HPV阳性（+）HNSCC。BCL-2家族抑制剂navitoclax已被证明可有效消除衰老细胞。我们评价了Palbociclib和Navitoclax联合治疗HPV-HNSCC的疗效。使用palbociclib处理3种HPV- HNSCC细胞系（CAL 27、HN 31、PCI 15 B）和3种HPV+ HNSCC细胞系（UPCI-SCC-090、UPCI-SCC-154、UM-SCC-47）。在所有HPV-细胞系中，给药导致磷酸化Rb（p-Rb）表达降低，并导致衰老表型证据，而HPV+细胞系对Rb或p-Rb的反应不一致，对palbociclib的反应也没有表现出衰老的形态学变化。此外，与未处理对照相比，palbociclib处理HPV-细胞可增加β-半乳糖苷酶蛋白表达和BCL-xL蛋白表达。β-半乳糖苷酶和BCL-xL的共表达一致地发生，表明衰老细胞中BCL-xL表达升高。与每种药物单独给药相比，palbociclib与navitoclax联合给药导致HPV-HNSCC细胞存活率降低，并导致HPV-细胞系凋亡水平升高。
We demonstrate that inhibition of cyclin dependent kinases 4/6 (CDK4/6) leads to senescence in human papillomavirus (HPV)-negative (−) head and neck squamous cell carcinoma (HNSCC), but not in HPV-positive (+) HNSCC. The BCL-2 family inhibitor, navitoclax, has been shown to eliminate senescent cells effectively. We evaluated the efficacy of combining palbociclib and navitoclax in HPV- HNSCC. Three HPV- HNSCC cell lines (CAL27, HN31, PCI15B) and three HPV+ HNSCC cell lines (UPCI-SCC-090, UPCI-SCC-154, UM-SCC-47) were treated with palbociclib. Treatment drove reduced expression of phosphorylated Rb (p-Rb) and phenotypic evidence of senescence in all HPV- cell lines, while HPV+ cell lines did not display a consistent response by Rb or p-Rb and did not exhibit morphologic changes of senescence in response to palbociclib. In addition, treatment of HPV- cells with palbociclib increased both β-galactosidase protein expression and BCL-xL protein expression compared to untreated controls in HPV- cells. Co-expression of p-galactosidase and BCL-xL occurred consistently indicating elevated BCL-xL expression in senescent cells. Combining palbociclib with navitoclax led to decreased HPV- HNSCC cell survival and led to increased apoptosis levels in HPV- cell lines compared to each agent given alone.