Lemur tyrosine kinase 2 (LMTK2) is a determinant of cell sensitivity to apoptosis by regulating the levels of the BCL2 family members

TY - JOUR

T1 - Lemur tyrosine kinase 2 (LMTK2) is a determinant of cell sensitivity to apoptosis by regulating the levels of the BCL2 family members

AU - Conti, Annalisa

AU - Majorini, Maria Teresa

AU - Fontanella, Enrico

AU - Bardelli, Alberto

AU - Giacca, Mauro

AU - Delia, Domenico

AU - Mano, Miguel

AU - Lecis, Daniele

PY - 2017/3/28

Y1 - 2017/3/28

N2 - Using a high-throughput approach, we identified lemur tyrosine kinase 2 (LMTK2) as a novel determinant of cell sensitivity to TRAIL. LMTK2 is a poorly characterized serine/threonine kinase believed to play a role in endosomal membrane trafficking and neuronal physiology, and recently found to be mutated in diverse tumor types. We show that LMTK2 silencing sensitizes immortalized epithelial cells and cancer cells to TRAIL, and this phenomenon is accompanied by changes in the expression of BCL2 family members. In epithelial cells, LMTK2 targeting causes the down-regulation of the BCL2 and BCL-xL anti-apoptotic proteins and the reciprocal up-regulation of the pro-apoptotic protein BIM, while, in cancer cells, LMTK2 knock-down reduces BCL2 without increasing BIM levels. We provide evidence that both BIM and BCL2 proteins are regulated by LMTK2 in a GSK3β- and PP1A-dependent manner and that their perturbation, together with BCL-xL reduction, determines an increased sensitivity not only to TRAIL, but also to other compounds. Overall, our findings suggest a broad function of LMTK2 in the regulation of the apoptotic pathway and highlight LMTK2 as a novel candidate target to increase the cytotoxic activity of chemotherapeutic compounds.

AB - Using a high-throughput approach, we identified lemur tyrosine kinase 2 (LMTK2) as a novel determinant of cell sensitivity to TRAIL. LMTK2 is a poorly characterized serine/threonine kinase believed to play a role in endosomal membrane trafficking and neuronal physiology, and recently found to be mutated in diverse tumor types. We show that LMTK2 silencing sensitizes immortalized epithelial cells and cancer cells to TRAIL, and this phenomenon is accompanied by changes in the expression of BCL2 family members. In epithelial cells, LMTK2 targeting causes the down-regulation of the BCL2 and BCL-xL anti-apoptotic proteins and the reciprocal up-regulation of the pro-apoptotic protein BIM, while, in cancer cells, LMTK2 knock-down reduces BCL2 without increasing BIM levels. We provide evidence that both BIM and BCL2 proteins are regulated by LMTK2 in a GSK3β- and PP1A-dependent manner and that their perturbation, together with BCL-xL reduction, determines an increased sensitivity not only to TRAIL, but also to other compounds. Overall, our findings suggest a broad function of LMTK2 in the regulation of the apoptotic pathway and highlight LMTK2 as a novel candidate target to increase the cytotoxic activity of chemotherapeutic compounds.

KW - Apoptosis regulation

KW - Cancer cell death

KW - Cytotoxic compounds

KW - LMTK2

KW - TRAIL

UR - http://www.scopus.com/inward/record.url?scp=85008957364&partnerID=8YFLogxK

U2 - 10.1016/j.canlet.2016.12.025

DO - 10.1016/j.canlet.2016.12.025

M3 - Article

C2 - 28040547

AN - SCOPUS:85008957364

SN - 0304-3835

VL - 389

SP - 59

EP - 69

JO - Cancer Letters

JF - Cancer Letters

ER -