title: Down Regulation of CLDND1 Induces Apoptosis in Breast Cancer Cells.
abstract: Identification of targets for apoptosis induction is important to provide novel therapeutic approaches in breast cancer. Our earlier studies showed that down regulation of protein kinase C δ (PKCδ) induces death in breast cancer cells. In this study we set out to identify previously unrecognized apoptosis regulators in breast cancer cells. To identify candidates, global expression analysis with microarray was performed after down regulation of PKCδ in the basal-like breast cancer cell lines MDA-MB-231, MDA-MB-468 and BT-549. Genes that were down regulated in all cell lines were further studied for survival-supporting effects. The claudin-like CLDND1 was singled out since several independent siRNAs targeting CLDND1 induced cell death in several cell lines. The cell death induced by CLDND1 knockdown was caspase-dependent, suggesting induction of apoptosis. Nuclear fragmentation, cleavage of caspase-3 and PARP and release of cytochrome C from the mitochondria upon CLDND1 depletion demonstrated involvement of the intrinsic apoptotic pathway. Inhibition of MEK1/2 and JNK further potentiated the cell death induction by CLDND1 knockdown. However, CLDND1 down regulation augmented ERK1/2 phosphorylation, which thereby may protect against the apoptosis inducing effects of CLDND1 down regulation. A concomitant inhibition of MEK1/2 suppresses the ERK1/2 phosphorylation and markedly potentiates the cell death following CLDND1 siRNA treatment. There is today little information on the function of CLDND1. These data provide novel information on CLDND1 and highlight it as a novel survival factor in basal-like breast cancer cell lines.
authors.affiliation: Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden.
authors.forename: Chandrani
authors.initials: C
authors.lastname: Achari
authors.affiliation: Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden.
authors.forename: Sofia
authors.initials: S
authors.lastname: Winslow
authors.affiliation: Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden.
authors.forename: Christer
authors.initials: C
authors.lastname: Larsson
mesh_terms: D017209:Apoptosis / Q000235:genetics*; D001483:Base Sequence; D001943:Breast Neoplasms / Q000473:pathology*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D057167:Claudins / Q000172:deficiency / Q000235:genetics*; D045304:Cytochromes c / Q000378:metabolism; D015536:Down-Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics; D008928:Mitochondria / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D059748:Proteolysis; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: C462524:CLDND1 protein, human; D057167:Claudins; D034741:RNA, Small Interfering; D045304:Cytochromes c; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3