Role of HSPA1L as a cellular prion protein stabilizer in tumor progression via HIF-1α/GP78 axis.

The cellular prion protein (PrPC) is associated with metastasis, tumor progression and recurrence; however, the precise mechanisms underlying its action is not well understood. Our study found that PrPCdegradation decreased tumor progression in colorectal cancer (CRC). In a CRC cell line and human CRC tissue exposed to hypoxia, induced heat-shock ...
70-kDa protein-1-like (HSPA1L) expression stabilized hypoxia-inducible factor-1α (HIF-1α) protein and promoted PrPCaccumulation and tumorigenicity in vivo. PrPCwas degraded via the proteasome pathway mediated by the ubiquitin-protein E3 ligase glycoprotein 78 (GP78), which interacts directly with PrPC. However, hypoxia-induced HSPA1L interacted with GP78 and inhibited its functions. HSPA1L knockdown facilitated the interaction of GP78 and PrPC, thereby increasing PrPCubiquitination. Thus, GP78 was identified as the ubiquitinase for PrPC, thereby revealing an essential mechanism that controls PrPClevels in CRC. Our results suggest that the HSPA1L/HIF-1α/GP78 axis has a crucial role in PrPCaccumulation during tumor progression.
Mesh Terms:
Carcinogenesis, Cell Culture Techniques, Colorectal Neoplasms, Disease Progression, Flow Cytometry, Gene Knockdown Techniques, HSP70 Heat-Shock Proteins, HT29 Cells, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Molecular Targeted Therapy, Prion Proteins, Proteasome Endopeptidase Complex, Proteolysis, RNA Interference, RNA, Small Interfering, Receptors, Autocrine Motility Factor, Signal Transduction, Ubiquitination
Oncogene
Date: Nov. 23, 2017
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