Cholesterol Auxotrophy as a Targetable Vulnerability in Clear Cell Renal Cell Carcinoma

Abstract

Clear cell renal cell carcinoma (ccRCC) is characterized by large intracellular lipid droplets containing free and esterified cholesterol; however, the functional significance of cholesterol accumulation in ccRCC cells is unknown. We demonstrate that, surprisingly, genes encoding cholesterol biosynthetic enzymes are repressed in ccRCC, suggesting a dependency on exogenous cholesterol. Mendelian randomization analyses based on 31,000 individuals indicate a causal link between elevated circulating high-density lipoprotein (HDL) cholesterol and ccRCC risk. Depriving ccRCC cells of either cholesterol or HDL compromises proliferation and survival in vitro and tumor growth in vivo; in contrast, elevated dietary cholesterol promotes tumor growth. Scavenger Receptor B1 (SCARB1) is uniquely required for cholesterol import, and inhibiting SCARB1 is sufficient to cause ccRCC cell-cycle arrest, apoptosis, elevated intracellular reactive oxygen species levels, and decreased PI3K/AKT signaling. Collectively, we reveal a cholesterol dependency in ccRCC and implicate SCARB1 as a novel therapeutic target for treating kidney cancer. Significance: We demonstrate that ccRCC cells are auxotrophic for exogenous cholesterol to maintain PI3K/AKT signaling pathway and ROS homeostasis. Blocking cholesterol import through the HDL transporter SCARB1 compromises ccRCC cell survival and tumor growth, suggesting a novel pharmacologic target for this disease. This article is highlighted in the In This Issue feature, p. 2945

Upregulation of SQLE Contributes to Poor Survival in Head and Neck Squamous Cell Carcinoma

“…Many cancer cell lines depend on exogenous cholesterol for their growth. For example, when lacking lipoprotein in serum, histiocytic lymphoma cells and clear cell renal cell carcinoma (ccRCC) cells die unless supplemented with exogenous cholesterol [29,30]. In addition, lower levels of LDLR but higher levels of SQLE are expressed in advanced-stage prostate cancer, revealing a greater dependence on endogenous cholesterol synthesis than uptake [31].…”

NPC1 Confers Metabolic Flexibility in Triple Negative Breast Cancer

“…In the absence of adequate LDL-derived cholesterol from the microenvironment, most cell types in normal physiology are able to produce cholesterol de novo through the cholesterol biosynthesis pathway [ 14 , 25 , 26 ]. However, recent studies identified “cholesterol auxotrophy”, the inability to survive without exogenous cholesterol, in varying types of cancers [ 27 , 28 ], suggesting cholesterol uptake as a targetable pathway. NPC1 specifically transports lysosomal cholesterol to the endoplasmic reticulum [ 29 ] where cellular cholesterol levels are sensed and controlled [ 17 , 30 ].…”

NPC1 confers metabolic flexibility in Triple Negative Breast Cancer

“…In the absence of adequate LDL-derived cholesterol from the microenvironment, most cell types in normal physiology are able to produce cholesterol de novo through the cholesterol biosynthesis pathway (14,25,26) . However, recent studies identified “cholesterol auxotrophy”, the inability to survive without exogenous cholesterol, in varying cancer subtypes (27,28) and suggest cholesterol uptake as a targetable pathway. NPC1 specifically transports lysosomal cholesterol to the endoplasmic reticulum (29) where cellular cholesterol levels are sensed and controlled (17,30) .…”

“…Random fields (25)(26)(27)(28)(29)(30) were analyzed and each cell was classified into 3 categories according to the main mitochondrial morphology (small, medium, elongated). For automated analysis of mitochondrial size, slides were scanned in a Zeiss LSM780 confocal microscope with 63X oil objective.…”