Targeting NPC1 in Renal Cell Carcinoma

Abstract

Rapidly proliferating cancer cells have a greater requirement for cholesterol than normal cells. Tumor cells are largely dependent on exogenous lipids given that their growth requirements are not fully met by endogenous pathways. Our current study shows that ccRCC cells have redundant mechanisms of cholesterol acquisition. We demonstrate that all major lipoproteins (i.e., LDL, HDL, and VLDL) have a comparable ability to support the growth of ccRCC cells and are equally effective in counteracting the antitumor activities of TKIs. The intracellular trafficking of exogenous lipoprotein-derived cholesterol appears to be distinct from the movement of endogenously synthesized cholesterol. De novo synthetized cholesterol is transported from the endoplasmic reticulum directly to the plasma membrane and to the acyl-CoA: cholesterol acyltransferase, whereas lipoprotein-derived cholesterol is distributed through the NPC1-dependent endosomal trafficking system. Expression of NPC1 is increased in ccRCC at mRNA and protein levels, and high expression of NPC1 is associated with poor prognosis. Our current findings show that ccRCC cells are particularly sensitive to the inhibition of endolysosomal cholesterol export and underline the therapeutic potential of targeting NPC1 in ccRCC.

Clear Cell Renal Cell Carcinoma: A Test Bench for Investigating Tumor Complexity

“…Here, basic researchers and clinicians from Italy, Japan, USA, Spain, South Africa, Sweden, Romania, and Germany present their findings from very different perspectives, i.e., the role of the complement system in the immune background of tumors [4], imagingbased biomarker identification [5], the relevance of the immune microenvironment [6,7], the influence of clock genes and the circadian rhythm in tumor therapy [8], the morphological/molecular characteristics of cystic CCRCCs [9], the single-cell RNA-sequencing signature of primary and metastatic neoplasms [10], an extensive review of tumor biomarkers in CCRCC [11], the nitric oxide cycle-related pathways of this tumor [12], the current trends and complications of partial and radical nephrectomy in CCRCC [13], the characteristics of the intratumor immune heterogeneity in non-metastatic tumors [14], the importance of NPC1 targeting in CCRCC [15], and a comparison between the efficacy of immune checkpoint inhibitors (ICI) and tyrosine kinase inhibitors (TKI)/everolimus in the adjuvant therapy of CCRCC [16].…”

“…Proliferating cancer cells have greater requirements for cholesterol than non-tumor cells, and Fazliyeva et al [15] show in their study that CCRCC cells have redundant mechanisms of cholesterol acquisition; for example, all major lipoproteins have comparable ability to support tumor cell growth and are equally effective in counteracting the antitumor activity of TKIs. Interestingly, the endolysosomal cholesterol transport regulated by the Niemann-Pick type C1 (NPC1) protein is a therapeutic target because this is a point where lipoproteins-derived cholesterol trafficking routes converge and may be simultaneously targeted in CCRCC patients.…”