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Vol. 16, Issue 3, 1555-1567, March 2005

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Golgi Fragmentation Is Associated with Ceramide-induced Cellular Effects

Wei Hu ^* , Ruijuan Xu ^*, Guofeng Zhang , Junfei Jin ^*, Zdzislaw M. Szulc , Jacek Bielawski , Yusuf A. Hannun , Lina M. Obeid ^*  , and Cungui Mao ^* 

^* Department of Medicine and Biochemistry, Medical University of South Carolina, Charleston, SC 28425; Department of Molecular Biology, Medical University of South Carolina, Charleston, SC 28425; Division of Bioengineering and Physical Sciences, National Institutes of Health, Bethesda, MD 20892; and Ralph H. Johnson Veterans Administration Hospital, Charleston, SC 29401-5799

Submitted July 15, 2004; Revised November 22, 2004; Accepted December 7, 2004
Monitoring Editor: Vivek Malhotra

Ceramide has been shown to cause anoikis, a subtype of apoptosis due to inadequate cell adhesion. However, the underlying mechanism is unclear. Herein, we report that D-e-C₆-ceramide (D-e-Cer), via generating sphingosine, disrupts the Golgi complex (GC), which is associated with various cellular effects, including anoikis. Treatment of HeLa cells with D-e-Cer caused cell elongation, spreading inhibition, rounding, and detachment before apoptosis (anoikis). In D-e-Cer–treated cells, glycosylation of 1 integrin in the GC was inhibited, thus its associated integrin receptors failed to translocate to the cell surface. Ceramide treatment also inhibited the reorganization of both microtubule and F-actin cytoskeletons, focal adhesions, and filopodia. These cellular effects were preceded by fragmentation of the Golgi complex. In contrast, L-e-C₆-ceramide (L-e-Cer), the enantiomer of D-e-Cer, failed to induce these cellular effects. Mass spectrometric analysis revealed that treatment HeLa cells with D-e-Cer but not L-e-Cer caused a >50-fold increase in the levels of sphingosine, a product of hydrolysis of ceramide. Treatment with D-e-sphingosine and its enantiomer, L-e-sphingosine, caused massive perinuclear vacuolization, Golgi fragmentation, and cell rounding. Together, these results suggest that sphingosine generated from hydrolysis of ceramide causes the GC disruption, leading to various cellular effects.

Address correspondence to: Cungui Mao (maoc{at}musc.edu).

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