AIM: CD44 and CD147 are associated with cancer metastasis and progression. We aimed to investigate the effects of CD44 or CD147 down-regulation on the metastatic ability of prostate cancer (CaP) cells, their docetaxel (DTX) responsiveness and potential mechanisms involved, using vitro and in vivo models.
METHODS: CD44 and CD147 were knocked down (KD) in PC-3M-luc CaP cells using short hairpin RNA. Expression of CD44, CD147, MRP2 (multi-drug resistance protein-2) and MCT4 (monocarboxylate tranporter-4) was evaluated using immunofluorescence and Western blotting. Cell proliferation and the DTX dose-response was measured by MTT and colony assays. The invasive potential was assessed using a matrigel chamber assay. Signal transduction proteins in the PI3K/Akt and MAPK/Erk pathways were assessed by Western blotting. An in vivo subcutaneous (s.c.) xenograft model was established to assess CaP tumorigenecity, lymph node metastases and DTX response.
RESULTS: CD44 and CD147 interact in CaP cells. KD of CD44 or CD147 decreased MCT4 and MRP2 expression, reduced CaP proliferation and invasive potential and enhanced DTX sensitivity. KD of CD44 or CD147 down-regulated p-Akt and p-Erk, the main signal modulators associated with cell growth and survival. In vivo, CD44 or CD147-KD PC-3M-luc xenografts displayed suppressed tumor growth with increased DTX responsiveness compared to control xenografts. Both CD44 and CD147 enhanced metastatic capacity and chemoresistance of CaP cells, potentially mediated by activation of the PI3K and MAPK pathways.
CONCLUSION: Selective targeting of CD44 or CD147 alone, or combined with DTX, may limit CaP metastasis and increase chemosensitivity, with promise for future CaP treatment.