Hedgehog signaling regulates drug sensitivity by targeting ABC transporters ABCB1 and ABCG2 in epithelial ovarian cancer

Abstract

A major challenge of successful chemotherapy in ovarian cancer is overcoming intrinsic or acquired multi-drug resistance caused by active drug efflux mediated by ATP-binding cassette (ABC) transporters. Regulation of these transporters in ovarian cancer is poorly understood. We have found that abnormal expression of the hedgehog (Hh) signaling pathway transcription factor Gli1 is involved in the regulation of ABC transporters ABCB1 and ABCG2 in ovarian cancer. Hh is a known regulator of cancer cell proliferation and differentiation in several other types of invasive and metastatic malignancies. Our work has demonstrated that Gli1 is abnormally activated in a portion of ovarian cancers. Inhibition of Gli1 expression decreases ABCB1 and ABCG2 gene expression levels and enhances the response of ovarian cancer cells to certain chemotherapeutic drugs. The underlying mechanism is a direct association of Gli1 with a specific consensus sequence located in the promoter region of ABCB1 and ABCG2 genes. This study provides new understanding of ABC gene regulation by Hh signaling pathway, which may lead to the identification of new markers to detect and to anticipate ovarian cancer chemotherapy drug sensitivity.

Hedgehog signaling pathway affects the sensitivity of hepatoma cells to drug therapy through the ABCC1 transporter

“…26 These findings are further supported by the observation that ABCB1 and ABCG2 promoter regions have the consensus sequence of Gli-binding site, and Gli-1 directly bound to the consensus GACCACCCA-like motif located in the promoter regions of ABCB1 and ABCG2 to regulate their transcription in B-cell lymphoma and ovarian cancer cells. 27,28 However, our results demonstrate that ABCC1 was highly expressed in Huh-7-DN and Huh-7-trans cells; in Figure 7 The effects of LDE225 and itraconazole on expression of Gli-1, Gli-2, and ABCC1 in Huh-7-DN subpopulation. Huh-7-DN cells were exposed to LDE225 or itraconazole at various concentrations as indicated for 24 h. mRNA levels of Gli-1, Gli-2, and ABCC1 in Huh-7-DN subpopulation were determined by quantitative RT-PCR, using untreated Huh-7 cells as a control.…”

Integration and bioinformatics analysis of DNA-methylated genes associated with drug resistance in ovarian cancer

“…The P-gp protein encoded by ABCB1 regulates the drug cumulative effect in tumour cells and eventually participates in the multidrug resistance process by being involved in drug transport across the membrane and in membrane stability maintenance (57); ABCG2 possesses ATP activity and is involved in biological processes, including drug transport and cell membrane stability (58). Chen et al (59) observed that ABCB1 and ABCG2 are involved in ovarian cancer drug resistance through the transcription factor Gli of the Hh signalling pathway. Gli expression inhibition may reduce ABCB1 and ABCG2 gene expression levels and strengthen the sensitivity of ovarian cancer to chemotherapy.…”

Hedgehog signaling in the pathogenesis of neuro-oncology diseases

“…Сигнальный путь HH через транскрипционный фактор GLI1 способен влиять на экспрессию генов ABC переносчиков ABCG2, MDR1, MRP1 и генов MVP и MGMT, принимающих участие в формировании химиорезистентности [53,90,91]. Показано, что GLI1 влияет на экспрессию MGMT, связываясь с GLI1-связывающим сайтом в его промотере [92].…”

“…Химиопрепараты и циклопамин значительно увеличивали гибель клеток и уровень апоптоза [53]. Аналогичные данные были продемонстрированы при ингибировании GLI1 в культуре клеток рака яичников [91].…”