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Akt activation increases cellular cholesterol by promoting the proteasomal degradation of Niemann-Pick C1


Null mutations of the Niemann-Pick type C1 (NPC1) gene cause NPC disease, a lysosomal storage disorder characterized by cholesterol accumulation in late endosomes (LE) and lysosomes (Ly). Nascent or mutated NPC1 is degraded through the ubiquitin-proteasome pathway, but how NPC1 degradation is regulated remains currently unknown. In the present study, we demonstrated a link between NPC1 degradation and the Akt (protein kinase B)/mTOR [mammalian (or mechanistic) target of rapamycin] signalling pathway in cervical cancer cell lines. We provided evidence that activated Akt/mTOR pathway increased NPC1 degradation by approximately 50% in C33A cells when compared with SiHa or HeLa cells. NPC1 degradation in C33A cells was reversed when Akt/mTOR activation was blocked by specific inhibitors or when mTORC1 (mTOR complex 1) was disrupted by regulatory associated protein of mTOR (Raptor) knockdown. Importantly, inhibition of the Akt/mTOR pathway led to decreased NPC1 ubiquitination in C33A cells, pointing to a role of Akt/mTOR in the proteasomal degradation of NPC1. Moreover, we found that NPC1 depletion in several cancer cell lines inhibited cell proliferation and migration. Our results uncover Akt as a key regulator of NPC1 degradation and link NPC1 to cancer cell proliferation and migration.

Type Journal
ISBN 1470-8728 (Electronic) 0264-6021 (Linking)
Authors Du, X. ; Zhang, Y. ; Jo, S. R. ; Liu, X. ; Qi, Y. ; Osborne, B. ; Byrne, F. L. ; Smith, G. C. ; Turner, N. ; Hoehn, K. L. ; Brown, A. J. ; Yang, H.;
Responsible Garvan Author Brenna Osborne
Published Date 2015-01-01
Published Volume 471
Published Issue 2
Published Pages 243-53
Status Published in-print
URL link to publisher's version
OpenAccess link to author's accepted manuscript version