The mitochondrial transport protein SLC25A43 affects drug efficacy and             drug-induced cell cycle arrest in breast cancer cell lines.
The mitochondria have been identified as key players of apoptosis, cell             proliferation and cell cycle regulation. However, the role of mitochondria in             breast cancer and treatment failure remains unclear. We have previously shown             a common deletion of the gene SLC25A43 in human epidermal growth factor receptor 2             (HER2)-positive breast cancer. This gene is coding for a mitochondrial inner membrane             transporter and, to date, little is known about the function of this protein.             We have also found that low protein expression of SLC25A43 significantly correlates             with a lower S phase fraction in HER2-positive breast cancer. The aim of this             study was to investigate whether knockdown (KD) of SLC25A43 could have an effect             on the cytotoxicity of different cytostatic drugs using MCF10A, MCF7 and BT-474             cells. Following siRNA-mediated KD of SLC25A43, one non-malignant and two breast             cancer cell lines were exposed to the anthracycline epirubicin or the taxane paclitaxel.             The HER2-positive breast cancer cells were also exposed to the targeted therapy             trastuzumab and dual exposure to trastuzumab and paclitaxel. We found that KD             of SLC25A43 resulted in a decreased cytotoxic effect of paclitaxel in the two             cancer cell lines (P<0.05). Further analysis of cell cycle phase distribution             showed that KD increased the paclitaxel-induced G2/M block in these two cell lines             (P<0.05). KD of SLC25A43 also reduced the inhibitory effect of trastuzumab             on cell proliferation in the HER2-positive cancer cell line BT-474 (P<0.05),             and the drug-induced G0/G1 block (P<0.05). Moreover, SLC25A43 influenced the             percentage of Ki-67-positive cells. Our findings demonstrate that the mitochondrial             protein SLC25A43 affects drug efficacy and cell cycle regulation following drug             exposure in breast cancer cell lines.
School of Health and Medical Sciences, Örebro University Hospital, SE-70185 Örebro, Sweden. marike.gabrielsson@oru.se
Marike
M
Gabrielson
Elisabet
E
Tina
D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D000970:Antineoplastic Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D054316:Biomarkers, Pharmacological / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D055785:Gene Knockdown Techniques; D006801:Humans; D061986:MCF-7 Cells; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D017239:Paclitaxel / Q000008:administration & dosage*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D000068878:Trastuzumab; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D054316:Biomarkers, Pharmacological; D017239:Paclitaxel; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; D025521:Tumor Suppressor Proteins; C573824:SLC25A43 protein, human; C508053:ERBB2 protein, human