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-b-gal activity, DcR2 and Dec1 expression, and senescence-associated secretary phenotype (SASP) such as proinflammatory cytokines interleukin (IL)-1a, 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-jB 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-b-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)-jB activity. These data indicated potential insights into therapeutic improvement with reinforcing TIS-related performance or overcoming SASP-induced resistance. (Cancer Sci 2013; 104: 1052-1061 R enal cell carcinoma (RCC) accounts for 2-3% of all malignant diseases in adults, with an incidence of 64 770 new cases and 13 570 deaths in the USA in 2012. (1) Clear cell RCC (ccRCC) is the major histologic subtype (about 80-90%). (2) Approximately 25-30% of RCC patients are diagnosed due to symptoms associated with metastatic disease. (3) Despite partial and radical nephrectomy offering goldstandard treatments to cure localized ccRCC patients, 20-40% of them eventually relapse after surgery. (4) mRCC, characterized by poor prognosis, is highly resistant to chemotherapy and radiotherapy. (5) Immunotherapy with either interleukin (IL)-2 or interferon (IFN), which was developed into an alternative treatment for mRCC patients with limited overall response rates of 21.0-23.2% to high-dose IL-2 and 11-16% to IFN, respectively, failed to show any significant overall survival benefit along with substantial toxicities. (6)(7)(8) Sunitinib is a multitargeted inhibitor of receptor tyrosine kinases (RTK) known to selectively inhibit several growth factor receptors, including vascular endothelial growth factor (VEGF) receptors (VEGFR1, VEGFR2 and VEGFR3), platelet-derived growth factor (PDGF) receptors (PDGFRa and PDGFRb), FLT3, KIT, RET and CSF1R. (9) Despite it being used mainly as a default antiangiogenic therapy against...
Klotho is an anti-aging protein predominantly expressed in renal tubular epithelial cells. Although Klotho was recently identified as a tumor suppressor gene in a variety of cancers, the potential role and molecular events for Klotho in renal cell carcinoma (RCC) remain obscure. In the present study, immunohistochemical staining in tissue microarrays containing 125 RCC samples showed that intratumoral Klotho levels were negatively correlated with tumor size, TNM stage and nuclear grade. The overall survival rate of RCC patients with high Klotho expression was significantly higher than that of patients with low Klotho expression. Functional analysis after gain and loss of Klotho expression revealed that Klotho blunted epithelial-mesenchymal transition and cellular migration and invasion in RCC. Also, no alteration of a-2,6-sialidase activity was found after Klotho overexpression in RCC. The molecular signals for this phenomenon involved the Klotho-mediated inhibition of PI3K ⁄ Akt ⁄ GSK3b ⁄ Snail pathway. Importantly, compared to localized RCC tissues, advanced RCC tissues exhibited low Klotho expression accompanied with high pAkt and Snail expression. These results indicate Klotho acts as a tumor suppressor by inhibiting PI3K ⁄ Akt ⁄ GSK3b ⁄ Snail signaling, thus suppressing epithelial-mesenchymal transition and tumor migration and invasion during RCC progression. As a result, Klotho might be used as a potential therapy for advanced RCC. (Cancer Sci 2013; 104: 663-671) R enal cell carcinoma (RCC) is the most common type of kidney cancer. It is the third most frequent malignancy within urological oncology, accounting for 2-3% of all cancers worldwide.(1) Although early detection approaches are available for localized RCC, approximately 25-30% of patients have undiagnosed with metastatic diseases.(2) Partial and radical nephrectomies remain the gold standard in treatment for localized RCC, and cytoreductive nephrectomy is often recommended before systemic treatment targeting invasiveness reduction and renal function preservation for metastatic diseases.(3) Nevertheless, 20-40% of RCC patients will relapse after resection depending on the tumor stage and grade.(4) Metastatic RCC (mRCC), which is uniquely resistant to chemotherapy and radiotherapy, has only a 26% 5-year survival. The therapeutic effectiveness of immunotherapy and antiangiogenic intervention is still controversial.(6) Moreover, present systemic therapies show limited overall survival benefit concomitant with substantial toxicities. Thus, explorations of molecular pathways for RCC tumorigenesis are likely to expand therapeutic options for mRCC.Klotho is an aging suppressor gene that has been shown to extend lifespan when overexpressed in mice.(7) Genetic ablation of the Klotho gene in mice leads to a syndrome closely resembling human aging that involves a shortened lifespan, growth arrest, premature thymic involution, arterial calcification, osteoporosis and emphysema.(7-9) The Klotho gene encodes a single-pass transmembrane protein of 135 kDa exp...
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