pH low insertion peptide mediated cell division cycle-associated protein 1 -siRNA transportation for prostatic cancer therapy targeted to the tumor microenvironment

Prostate cancer (PCa) is a common malignancy in male urinary system. Cell division cycle-associated protein 1 (CDCA1) is expressed highly in many cancer cells. Yet, whether CDCA1 play an important role in PCa progression is uncertain. pH low insertion peptide (pHLIP), a PH-induced transmembrane structure, can pass through the cell membrane into intracellular in an acidic environment. In this study, we try to confirm the expression status of CDCA1 in the PCa patients' tissues and PCa cell line. In addition, to make the CDCA1-siRNA efficiently targeting the PCa cells, pHLIP and CDCA1-siRNA were combined with disulfide bond to become effector molecules. By the characteristics of the pHLIP allosteric occurring in cancer tissue acidic microenvironment, CDCA1-siRNA may be transported specificity into prostatic cancer cells and released in the cytoplasm. The interference effect of the effector molecules on the CDCA1 was detected in vitro and in vivo. The results showed that CDCA1 was highly expressed in PCa cell line and human PCa clinical samples. Knock down CDCA1 significantly inhibit the growth and promote the apoptosis of prostatic cancer cells. In the intracellular translocation experiment, CDCA1-siRNA could be delivered into cytoplasma at pH 6.2, but not at pH 7.4. In the in vivo test, the tumor size was reduced obviously in the NOD/SCID mice treated with pHLIP-CDCA1-siRNA compared to the CDCA1-siRNA and the bioluminescent signal of Cy5-pHLIP-CDCA1-siRNA was focused detected in the tumor site. Our findings indicated that CDCA1 might be a very key molecule regulating survival and proliferation of PCa. pHLIP-CDCA1-siRNA might be a promising targeting therapy for PCa.