CircTHSD4 promotes the malignancy and docetaxel (DTX) resistance in prostate cancer by regulating miR-203/HMGA2 axis

Objective:Circular ribose nudeic acids(circRNAs)are implicated in tumor progression and drug resistance of prostate cancer(PCa).The current work explored the function of circ_0005203(aircTHSD4)in the malignancy and docetaxel(DTX)resistance of PCa.Methods:circTHSD4 expression within PCa as well as matched non-carcinoma samples was measured through real time reverse transcription quantitative polymerase chain reaction(RT-qPCR).In addition,a subcellular fraction assay was conducted to determine circTHSD4 subcellular localization within PCa cells.In addition,we performed a Western blot(WB)assay to detect high mobility.group A2 protein(HMGA2)levels.Besides,functional associations of two molecules were investigated through dual luciferase reporter assay.Cell Counting Kit(CCK)-8,colony formation together with Transwell assay was conducted to assess malignant phenotypes of PCa cells,whereas flow cytometry was performed to determine cell apoptosis.Furthermore,a xenograft mouse model was constructed to verify the effect of circTHSD4 on the carcinogenesis of PCa cells.Results:According to RT-qPCR results,circTHSD4 was up-regulated within PCa tissues and cells,which predicted the dismal prognostic outcome of PCa cases.circTHSD4 silencing within PCa cells markedly suppressed cell growth,migration,and colony fomation.circTHSD4 silencing remarkably elevated PCa cell apoptosis and carcinogenesis within the xenograft model.Further,circTHSD4 silencing enhanced docetaxel(DTX)sensitivity in PCa cells.Furthermore,we demonstrated that circTHSD4 modulated the malignancy of PCa cells by regulating HMGA2 expression through sponging miR 203.Conclusion:Together,our findings suggest that cirCTHSD4 overexpression could promote the malignant phenotype and DTX resistance in PCa through the regulation of the miR 203/HMGA2 axis.

Ritonavir reverses resistance to docetaxel and cabazitaxel in prostate cancer cells with acquired resistance to docetaxel

Aim:Docetaxel is a microtubule-stabilizing drug used for the treatment of several cancers,including prostate cancer.Resistance to docetaxel can either occur through intrinsic resistance or develop under therapeutic pressure,i.e.,acquired resistance.A possible explanation for the occurrence of acquired resistance to docetaxel is increased drug efflux via P-glycoprotein(P-gp)drug transporters.Methods:We have generated docetaxel-resistant cell lines DU-145DOC10 and 22Rv1DOC8 by exposing parental cell lines DU-145DOC and 22Rv1 to increasing levels of docetaxel.Gene expression levels between DU-145DOC10 and 22Rv1DOC8 were compared with those of their respective originator cell lines.Both parental and resistant cell lines were treated with the taxane drugs docetaxel and cabazitaxel in combination with the P-gp/CYP3A4 inhibitor ritonavir and the P-gp inhibitor elacridar.Results:In the docetaxel-resistant cell lines DU-145DOC10 and 22Rv1DOC8,the ABCB1(P-gp)gene was highly up-regulated.Expression of the P-gp protein was also significantly increased in the docetaxel-resistant cell lines in a Western blotting assay.The addition of ritonavir to docetaxel resulted in a return of the sensitivity to docetaxel in the DU-145DOC10 and 22Rv1DOC8 to a level similar to the sensitivity in the originator cells.We found that these docetaxel-resistant cell lines could also be re-sensitized to cabazitaxel in a similar manner.In a Caco-2 P-gp transporter assay,functional inhibition of P-gp-mediated transport of docetaxel with ritonavir was demonstrated.Conclusion:Our results demonstrate that ritonavir restores sensitivity to both docetaxel and cabazitaxel in docetaxel-resistant cell lines,most likely by inhibiting P-gp-mediated drug efflux.