Inhibition of MCL‐1 by obatoclax sensitizes Sp2/0‐Ag14 hybridoma cells to glutamine deprivation‐induced apoptosis. (15th July 2015)

• Record Type: Journal Article
• Authors: Harnett, Curtis C.; Abusneina, Abdelmuhsen; Clément, Julie; Gauthier, Eric R.
• Is Part Of: Cell biochemistry and function. Volume 33:Number 5(2015:Jul.)
• Page Start: 334
• Page End: 340
• Publication Date: 2015-07-15
• Subjects: Cytochemistry -- Periodicals; Cell metabolism -- Periodicals; Biochemistry -- Periodicals; Cytology -- Periodicals; 572
• DOI: 10.1002/cbf.3121
• Languages: English
• ISSNs: 0263-6484

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>For several cancer cell types, the lack of an adequate supply of the amino acid<sc>l</sc>‐glutamine (Gln) triggers apoptosis, a phenomenon termed Gln addiction. In this report, we examined the role of the anti‐apoptotic proteins of the B‐cell lymphoma 2 (BCL‐2) protein family in the survival of Sp2/0‐Ag14 (Sp2/0) mouse hybridoma cells, a cell line that undergoes apoptosis within minutes of Gln deprivation. Western blot analysis revealed that myeloid cell leukaemia 1 (MCL‐1) was expressed at much higher levels than BCL‐2, B‐cell lymphoma extra‐large and BCL‐2‐like protein 2 making it the prominent pro‐survival BCL‐2 family member in this hybridoma. Gln deprivation triggered a progressive decrease in MCL‐1 protein levels, which coincided with the decrease in Sp2/0 cell survival. Moreover, Sp2/0 cells were much more sensitive to the broad Bcl‐2 homology domain‐3 (BH3) mimetic obatoclax (which targets MCL‐1) than to the more selective drug ABT‐737 (which does not target MCL‐1). Finally, we show that obatoclax sensitizes Sp2/0 cells to apoptosis following Gln starvation. All together, the data presented here reveal that modulation of the pro‐survival protein MCL‐1 is an important step in the sequence of events leading to the initiation of apoptosis in Gln‐starved Sp2/0 cells. Cancer cells require an adequate supply of<sc>l</sc>‐glutamine for their survival. Using a mouse hybridoma cell line that is exquisitely sensitive to glutamine starvation, we show that the levels of the pro‐survival BCL‐2 family protein MCL‐1 decrease upon glutamine starvation in a manner that correlates with the loss of cell viability. Moreover, inhibiting MCL‐1 with the drug obatoclax sensitizes hybridoma cells to glutamine starvation. Thus, in some cancer cells, glutamine starvation triggers the inactivation of pro‐survival proteins. Our data suggest that the combined inhibition of glutamine biosynthesis pathways and BCL‐2 proteins may prove effective against some cancers. Copyright © 2015 John Wiley & Sons, Ltd.</p> </abstract>