Reduction of full-length transglutaminase 2 (TG2-L) expression decreases cisplatin chemoresistance in an MCF-7 model of hormone-positive breast cancer


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Peter Coussons1,Ebidor Lawani-Luwaji1,Claire Pike1
1Anglia Ruskin University

Abstract

Background

Cisplatin is a highly effective chemotherapeutic drug that has the unfortunate downside of rapidly inducing chemotherapeutic resistance. Although it can be effective in the treatment of hormone-negative breast cancer, cisplatin has been less effective in the treatment of hormone-positive breast cancer. The highly pleiotropic enzyme, tissue transglutaminase 2 (TG2), is overexpressed in many cancers, where it is involved in diverse cellular functions including cell proliferation, cell cycle control, endocytosis, apoptosis and chemoresistance. TG2 exists mainly as a full-length “long” form (TG2-L), and a truncated “short” (TG2-S) form, which can modulate opposing functions. For example, while TG2-L subdues cell differentiation and supports cell survival, TG2-S promotes cell death. Here, we investigate whether modulation of TG2 expression might be a route to reducing cisplatin chemoresistance in hormone-positive breast cancer cells.

Method

In order to raise or lower TG2 expression, cisplatin-sensitive and cisplatin-resistant MCF-7 breast cancer cells were treated for up to 72 hours with non-toxic doses of either retinoic acid (+), or the TG2 inhibitor, cystamine (-), or anti-TG2 siRNA (-), respectively. Cells were then exposed to clinically relevant doses of cisplatin for a further 24 hours. MTT assay measured cellular viability, flow cytometry measured levels of apoptosis and necrosis, and Western blot analysis measured TG2 expression.

Results

Retinoic acid treatment of cells induced overexpression of TG2-L, promoting cell survival and increased cisplatin chemoresistance in all cases. Conversely, both cystamine and anti-TG2 siRNA treatment selectively suppressed TG2-L expression (with little effect on TG2-S expression), reducing cisplatin chemoresistance to basal control levels, without affecting cell viability.

Conclusion

The model suggests that limiting levels of TG2 expression, either by restricting retinoid availability, or through pharmacological intervention with TG2 inhibitors could improve cisplatin effectiveness in the treatment of hormone-positive breast cancer.