Abstract
We previously reported that nelfinavir (NFV) induces G(1) cell-cycle block and apoptosis selectively in liposarcoma cell lines due to increased SREBP-1 (sterol regulatory element binding protein-1) expression in the absence of increased transcription. We postulate that NFV interferes with regulated intramembrane proteolysis of SREBP-1 and ATF6 (activating transcription factor 6). Time-lapse, confocal microscopic studies show that NFV inhibits the nuclear translocation of full-length SREBP-1-EGFP and ATF6-EGFP fusion proteins. siRNA-mediated knockdown of site-1 protease (S1P) and/or site-2 protease (S2P) leads to inhibition of SREBP-1 intracellular trafficking to the nucleus and reduces liposarcoma cell proliferation. Treatment of LiSa-2 liposarcoma cells with 3,4-dichloroisocoumarin, a serine protease inhibitor of S1P, did not affect SREBP-1 processing. In contrast, 1,10-phenanthroline, an S2P-specific inhibitor, reproduces the molecular and biological phenotypes observed in NFV-treated cells, which implicates S2P as a target of NFV. In vivo evaluation of NFV in a murine liposarcoma xenograft model leads to inhibition of tumor growth without significant toxicity. NFV-induced upregulation of SREBP-1 and ATF6 results from inhibition of S2P, which together with S1P mediates regulated intramembrane proteolysis from their precursor to their transcriptionally active forms. The resulting endoplasmic reticulum (ER) stress and concurrent inhibition of the unfolded protein response induce caspase-mediated apoptosis. These results provide new insight into the mechanism of NFV-mediated induction of ER stress and cell death in liposarcomas and are the first to report targeting S2P for cancer therapy.
Highlights
The HIV protease inhibitor (PI) nelfinavir (NFV; Viracept) has shown promising anticancer activity via the induction of apoptotic cell death, induction of endoplasmic reticulum (ER) stress and autophagy, inhibition of epidermal growth factor receptor– and insulin-like growth factor receptor–mediated PI3K/Akt activation [1,2,3,4], and induction of chemoand radiosensitization [5]
We hypothesized that NFV would inhibit liposarcoma growth because HIV PI use is linked to a clinical syndrome of peripheral lipoatrophy known as "HIV protease-induced lipodystrophy syndrome" [10]
We show that NFV-induced upregulation of sterol regulatory element binding protein-1 (SREBP-1) and activating transcription factor 6 (ATF6) results from inhibition of site-2 protease (S2P), leading to prevention of intracellular transport of mature SREBP-1 and ATF6 to the nucleus
Summary
The HIV protease inhibitor (PI) nelfinavir (NFV; Viracept) has shown promising anticancer activity via the induction of apoptotic cell death, induction of endoplasmic reticulum (ER) stress and autophagy, inhibition of epidermal growth factor receptor– and insulin-like growth factor receptor–mediated PI3K (phosphoinositide 3kinase)/Akt activation [1,2,3,4], and induction of chemoand radiosensitization [5]. We hypothesized that NFV would inhibit liposarcoma growth because HIV PI use is linked to a clinical syndrome of peripheral lipoatrophy known as "HIV protease-induced lipodystrophy syndrome" [10]. In this syndrome, adipocyte apoptosis is observed and associated with alteration of sterol regulatory element binding protein-1 (SREBP-1) expression [11,12,13]
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