Abstract PR04: HIF-2{alpha} dependent lipid storage promotes endoplasmic reticulum homeostasis in clear cell renal cell carcinoma

Clear cell renal cell carcinoma (ccRCC) is the most common form of renal cancer, defined pathologically by abundant intracellular lipid droplets (LDs) that impart the clear cell phenotype, and molecularly by constitutive activation of the hypoxia inducible factors (HIFs). The primary aim of this study was to identify the mechanisms driving enhanced neutral lipid storage and the function of this phenotype in ccRCC. Our work demonstrates that HIF-2α promotes neutral lipid storage in ccRCC through up-regulation of the LD coat protein PLIN2. Expression profiling in multiple cohorts of primary ccRCC and normal kidney samples revealed that PLIN2 was overexpressed in all stages of disease and correlated with constitutive activation of HIF-2α, but not HIF-1α. Using ccRCC cell lines, 3D tumor spheroids, and tumor xenografts, we showed that HIF-2α dependent PLIN2 expression was required for neutral lipid storage and tumor cell viability. We demonstrated, for the first time, that PLIN2 dependent lipid storage promoted ccRCC tumor growth by maintaining integrity of the endoplasmic reticulum (ER), an organelle that is functionally and physically associated with LDs. Recent work indicates that cellular transformation commits tumors to growth programs that strain ER homeostasis, including elevated protein and lipid synthesis. Such ER stress is exacerbated by conditions of oxygen and nutrient deprivation characteristic of solid tumor microenvironments, which further d...
Source: Molecular Cancer Research - Category: Cancer & Oncology Authors: Tags: Autophagy and Metabolic Stress in Cancer: Oral Presentations - Proffered Abstracts Source Type: research