RESUMO
Recent studies have reported that TUBB3 overexpression is involved in docetaxel (DTX) resistance in prostate cancer (PCa). The aim of this study was to clarify the role of TUBB3 in DTX and cabazitaxel (CBZ) resistance, and cross-resistance between DTX and CBZ in PCa. We analyzed the effect of TUBB3 knockdown on DTX and CBZ resistance and examined the interaction between TUBB3 and PTEN. We also investigated the role of phosphoinositide 3-kinases (PI3K) inhibitor (LY294002) in DTX and CBZ resistance. TUBB3 expression was upregulated in DTX-resistant and CBZ-resistant cells. TUBB3 knockdown re-sensitized DTX-resistant cells to DTX and CBZ-resistant cells to CBZ. Additionally, TUBB3 knockdown re-sensitized DTX-resistant cell lines to CBZ, indicating that TUBB3 mediates cross-resistance between DTX and CBZ. Knockdown of TUBB3 enhanced PTEN expression, and PTEN knockout enhanced TUBB3 expression. LY294002 suppressed TUBB3 expression in DTX-resistant and CBZ-resistant cell lines. LY294002 re-sensitized DTX-resistant cell lines to DTX and CBZ-resistant cell lines to CBZ. These results suggest that TUBB3 is involved in DTX resistance and CBZ resistance. A combination of LY294002/DTX and that of LY294002/CBZ could be potential strategies for PCa treatment.
Assuntos
Antineoplásicos/farmacologia , Docetaxel/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias da Próstata/genética , Taxoides/farmacologia , Tubulina (Proteína)/genética , Linhagem Celular Tumoral , Cromonas/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Técnicas de Silenciamento de Genes , Humanos , Masculino , Morfolinas/farmacologia , PTEN Fosfo-Hidrolase/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Ligação Proteica , Tubulina (Proteína)/metabolismoRESUMO
We isolated and characterized four new PKCdelta isoforms, PKCdeltaIV, deltaV, deltaVI, and deltaVII, specifically expressed in the mouse testis. These isoforms possess neither V1 nor C2-like domains. Moreover, PKCdeltaVI and deltaVII have a different last exon as their V5 domain. The transcription of PKCdeltaIV, deltaV, deltaVI, and deltaVII is initiated from the same site in the upstream region of exon4 of the PKCdelta gene. They are expressed exclusively in the testis in an age-dependent manner. PKCdeltaIV and deltaV are expressed in spermatids with sperm maturation stage-specific manner, and that PKCdeltaVI and deltaVII are expressed in spermatogonia and spermatocytes.