Abstract
Clear cell renal cell carcinoma (ccRCC) is the most common and lethal form of urological cancer diagnosed globally. Mutations of the von Hippel-Lindau (VHL) tumor-suppressor gene and the resultant overexpression of hypoxia-inducible factor (HIF)-1α protein are considered hallmarks of ccRCC. Persistently activated HIF-1α is associated with increased cell proliferation, angiogenesis, and epithelial–mesenchymal transition (EMT), consequently leading to ccRCC progression and metastasis to other organs. However, the VHL status alone cannot predict the differential sensitivity of ccRCC to cancer treatments, which suggests that other molecular differences may contribute to the differential response of ccRCC cells to drug therapies. In this study, we investigated the response to metformin (an antidiabetic drug) of two human ccRCC cell lines Caki-1 and Caki-2, which express wild-type VHL. Our findings demonstrate a differential response between the two ccRCC cell lines studied, with Caki-2 cells being more sensitive to metformin compared to Caki-1 cells, which could be linked to the differential expression of HIF-1α despite both cell lines carrying a wild-type VHL. Our study unveils the therapeutic potential of metformin to inhibit the progression of ccRCC in vitro. Additional preclinical and clinical studies are required to ascertain the therapeutic efficacy of metformin against ccRCC.
Highlights
Renal cell carcinoma (RCC) is the third most common urological cancer and the sixth leading cause of cancer deaths in the United States [1,2,3,4]
For the management of recurrent or metastatic Clear cell renal cell carcinoma (ccRCC), targeted drug therapy is preferred; this includes the use of tyrosine kinase inhibitors such as sunitinib, sorafenib, axitinib and pazopanib; mammalian target of rapamycin inhibitors such as temsirolimus and everolimus; and monoclonal antibodies such as bevacizumab, which targets vascular endothelial growth factor (VEGF) [9,10]
To explore the underlying molecular mechanism(s) involved in the antineoplastic effects of metformin in Caki-1 and Caki-2 cell lines, we investigated the impact of metformin treatment on various crucial signaling pathways involved in the progression of ccRCC: hypoxia-inducible factor (HIF)-1α, AMPK, Akt/mammalian target of rapamycin (mTOR)
Summary
Renal cell carcinoma (RCC) is the third most common urological cancer and the sixth leading cause of cancer deaths in the United States [1,2,3,4]. The renal cancer cells are extremely proliferative and metastatic, and account for 3.8% of all new cancers [1,3]. Clear cell renal cell carcinoma (ccRCC) is the most common subtype of RCC and accounts for approximately 70–75% of all cases [5]. For the management of recurrent or metastatic ccRCC, targeted drug therapy is preferred; this includes the use of tyrosine kinase inhibitors such as sunitinib, sorafenib, axitinib and pazopanib; mammalian target of rapamycin (mTOR) inhibitors such as temsirolimus and everolimus; and monoclonal antibodies such as bevacizumab, which targets vascular endothelial growth factor (VEGF) [9,10]. In addition to tyrosine kinase inhibitors, immunotherapy using nivolumab and interferon-α are considered to be the standard
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