Hydroxychloroquine Potentiates Apoptosis Induced by PPARα Antagonist in 786-O Clear Cell Renal Cell Carcinoma Cells Associated with Inhibiting Autophagy

Abstract

Clear cell renal cell carcinoma (ccRCC) is the major pathological pattern of renal cell carcinoma. The ccRCC cells exhibit a certain degree of inherent drug resistance due to some genetic mutations. In recent years, peroxisome proliferator-activated receptor-α (PPARα) antagonists have been reported as a targeted therapeutic drug capable of inducing apoptosis and cell cycle arrest in the ccRCC cell line. Autophagy, which can be induced by stress in eukaryotic cells, plays a complex role in the proliferation, survival, and death of tumor cells. In our study, we found that the expression of PPARα was low in highly differentiated ccRCC tissues and 786-O cell line but high in poorly differentiated ccRCC tissues. The level of PPARα expression in ccRCC tissues is correlated to the grade of differentiation, but not to the sex or age of ccRCC patients. The findings also revealed that the PPARα antagonist GW6471 can lower cell viability and induce autophagy in the 786-O ccRCC cell line. This autophagy can be inhibited by hydroxychloroquine. When treated with a combination of hydroxychloroquine and GW6471, the viability of the 786-O cells was decreased further when compared to the treatment with GW6471 or hydroxychloroquine alone, and apoptosis was promoted. Meanwhile, when human kidney 2 cells were cotreated with hydroxychloroquine and GW6471, cell viability was only slightly influenced. Hence, our finding indicates that the combination of GW6471 and hydroxychloroquine may constitute a novel and potentially effective treatment for ccRCC. Furthermore, this approach is likely to be safe owing to its minimal effects on normal renal tissues.

WY-14643 attenuates lipid deposition via activation of the PPARα/CPT1A axis by targeting Gly335 to inhibit cell proliferation and migration in ccRCC

“…Considering abnormal lipid accumulation in ccRCC, in this study, WY-14,643 was administered to ccRCC cells. Although 786-O r cells did not show any significant effects on viability after treatment with WY-14,643 at concentrations less than 100 µM in a previous report [45], this is not inconsistent with the above results. In the current study, in ccRCC cells, cell viability was slightly affected after 100 µM WY-14,643 was applied, while 200 µM WY-14,643 treatment exerted an obvious antiproliferative effect.…”

“…Here, the anticancer effects of PPARα agonism by WY-14,643 were reported in ccRCC for the first time. Application of WY-14,643 at a higher concentration resulted in a more pronounced anticancer effect in ccRCC in comparison with a previous study [ 45 ]. In addition, in existing studies on tumors, the functions of PPARα have received little attention; conversely, the current study provides a possible mechanism by which PPARα regulates lipid metabolism and highlights the anticancer effect of WY-14,643 in ccRCC.…”