Sunitinib induces cellular senescence via p53/Dec1 activation in renal cell carcinoma cells

• Published in: Cancer science 2013-08, Vol.104 (8), p.1052-1061
• Main Authors: Zhu, Yu, Xu, Le, Zhang, Jianping, Hu, Xiaoyi, Liu, Yujun, Yin, Hankun, Lv, Tao, Zhang, Heng, Liu, Li, An, Huimin, Liu, Haiou, Xu, Jiejie, Lin, Zongming
• Format: Article
• Language: English
• Subjects: Carcinoma, Renal Cell - drug therapy; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - metabolism; Carcinoma, Renal Cell - pathology; Cell Cycle Checkpoints - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Cellular Senescence - drug effects; Disease Progression; DNA Damage; G1 Phase - drug effects; Humans; Indoles - pharmacology; Interleukins - genetics; Interleukins - metabolism; Kidney Neoplasms - drug therapy; Kidney Neoplasms - genetics; Kidney Neoplasms - metabolism; Kidney Neoplasms - pathology; NF-kappa B - genetics; NF-kappa B - metabolism; Original; Proto-Oncogene Proteins c-raf - genetics; Proto-Oncogene Proteins c-raf - metabolism; Pyrroles - pharmacology; S Phase - drug effects; Sunitinib; Tumor Necrosis Factor Decoy Receptors - genetics; Tumor Necrosis Factor Decoy Receptors - metabolism; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.12176

Although multitargeted tyrosine kinase inhibitor sunitinib has been used as first‐line therapeutic agent against metastatic renal cell carcinoma (mRCC), the molecular mechanism and functional role per se for its therapeutic performance remains obscure. Our present study revealed that sunitinib‐treated RCC cells exhibit senescence characteristics including increased SA‐β‐gal activity, DcR2 and Dec1 expression, and senescence‐associated secretary phenotype (SASP) such as proinflammatory cytokines interleukin (IL)‐1α, IL‐6 and IL‐8 secretion. Moreover, sunitinib administration also led to cell growth inhibition, G1‐S cell cycle arrest and DNA damage response in RCC cells, suggesting therapeutic significance of sunitinib‐induced RCC cellular senescence. Mechanistic investigations indicated that therapy‐induced senescence (TIS) following sunitinib treatment mainly attributed to p53/Dec1 signaling activation mediated by Raf‐1/NF‐κB inhibition in vitro. Importantly, in vivo study showed tumor growth inhibition and prolonged overall survival were associated with increased p53 and Dec1 expression, decreased Raf‐1 and Ki67 staining, and upregulated SA‐β‐gal activity after sunitinib treatment. Immunohistochemistry analysis of tumor tissues from RCC patients receiving sunitinib neoadjuvant therapy confirmed the similar treating phenotype. Taken together, our findings suggested that sunitinib treatment performance could be attributable to TIS, depending on p53/Dec1 activation via inhibited Raf‐1/nuclear factor (NF)‐κB activity. These data indicated potential insights into therapeutic improvement with reinforcing TIS‐related performance or overcoming SASP‐induced resistance.