Suppression of the ATP-binding cassette transporter ABCC4 impairs neuroblastoma tumour growth and sensitises to irinotecan in vivo

Abstract

The ATP-binding cassette transporter ABCC4 (Multidrug resistance protein 4, MRP4) mRNA level is a strong predictor of poor clinical outcome in neuroblastoma which may relate to its export of endogenous signaling molecules and chemotherapeutic agents. We sought to determine whether ABCC4 contributes to development, growth, and drug response in neuroblastoma in vivo. In neuroblastoma patients, high ABCC4 protein levels were associated with reduced overall survival. Inducible knockdown of ABCC4 strongly inhibited the growth of human neuroblastoma cells in vitro and impaired the growth of neuroblastoma xenografts. Loss of Abcc4 in the Th-MYCN transgenic neuroblastoma mouse model did not impact tumor formation, however Abcc4-null neuroblastomas were strongly sensitized to the ABCC4 substrate drug irinotecan. Our findings demonstrate a role for ABCC4 in neuroblastoma cell proliferation and chemoresistance and provide rationale for a strategy where inhibition of ABCC4 should both attenuate the growth of neuroblastoma and sensitize tumors to ABCC4 chemotherapeutic substrates.

p53 haploinsufficiency and increased mTOR signalling define a subset of aggressive hepatocellular carcinoma

“…45,46 Abcc4 has thus far been reported to have close relations with breast cancer, colorectal adenoma, acute lymphoblastic leukaemia, osteosarcoma, and pancreatic ductal adenocarcinoma in terms of proliferation and metastasis. [47][48][49][50][51][52] However, the function of Abcc4 in HCC has been rarely reported. In this study, we found that (1) Abcc4 was significantly overexpressed in HCC tumours with p53 (haplo)deficiency and Tsc1 deficiency; (2) Abcc4 expression was also increased in p53-deficient liver tissue compared with wild-type liver tissue; (3) Abcc4 expression was highly increased in HCC tissue compared with adjacent tissue from the same patient, and increased Abcc4 expression was positively associated with poor survival in patients with HCC with mutated p53 rather than wild-type p53; and (4) Abcc4 was positively associated with cell proliferation and metastasis in HCC and primary liver cells.…”

Discovery of Novel Symmetrical 1,4-Dihydropyridines as Inhibitors of Multidrug-Resistant Protein (MRP4) Efflux Pump for Anticancer Therapy

“…Contrasting the known efflux pumps P-gp, MRP1, and MRP2, MRP4 displays a symmetrical molecular framework and recently became an attractive target for cancer therapy because it transports several anticancer drugs not similar to the older known efflux pumps [24,25]. Expression of MRP4 was recently found in osteosarcoma, lymphoma, neuroblastoma, medulloblastoma as well as epithelial ovarian, clear-cell renal cell, and pancreatic cancer, where it has been associated with cell proliferation, tumor growth, and aggressiveness of the disease [26][27][28][29][30][31][32][33]. The regulation of critical pathways that drive the disease is attributed to the unique ability of MRP4 to transport endogenous signaling molecules such as cAMP, which also might affect the transporter's suggested impact on cellular differentiation processes within the hematopoietic system [34][35][36].…”

Increased ABCC4 Expression Induced by ERRα Leads to Docetaxel Resistance via Efflux of Docetaxel in Prostate Cancer

“…It has been reported that ABCC4 mRNA/protein expression was upregulated, and it was an important determinant of docetaxel resistance in PCa (17,27,41,42). Recently, the inhibition of ABCC4 is confirmed as a potential cure for neuroblastoma by inhibiting tumor proliferation and sensitizing to chemotherapeutic drug (18). Notably, increased ABCC4 expression has a strong correlation with multidrug resistance in PCa (28,43).…”

“…The protein encoded by ABCC4 is an important member of the ATP-binding cassette (ABC) membrane transporter family which can transport various molecules across extra/intra cellular membranes, and is involved in the export of endogenous signaling molecules and chemotherapeutic agents ( 18 , 19 ) and the transport of steroid hormones ( 20 ). The inhibition of ABCC4 has been shown to be beneficial for atherothrombotic disease due to its involvement in vascular biology and in platelet functions ( 21 – 23 ).…”