Previous studies have demonstrated that adipocytes promote prostate cancer (PCa) cell progression, which facilitates the development of PCa into castration-resistant prostate cancer (CRPC); however, the underlying mechanisms are still not fully understood. Matrix metalloproteinases (MMPs) are a group of proteases responsible for the degradation of extracellular matrix (ECM) and the activation of latent factors. In our study, we detected that MMP11 expression was increased in PCa patients and that a high level of MMP11 was correlated with poor prognosis. Furthermore, siRNA knockdown of MMP11 in CRPC cells not only blocked the delipidation and dedifferentiation of mature adipocytes but also reduced the lipid uptake and utilization of CRPC cells in a cell co-culture model. The number of mitophagosomes and the expression level of Parkin were increased in MMP11-silenced CRPC cells. Moreover, we found that simultaneous downregulation of MMP14 and MMP11 expression may benefit patient survival. Indeed, MMP11/14 knockdown in CRPC cells significantly decreased lipid metabolism and cell invasion, at least partly through the mTOR/HIF1α/MMP2 signaling pathway. Importantly, MMP11/14 knockdown dramatically delayed tumor growth in a xenograft mouse model. Consistently, the decreased lipid metabolism, Ki67 and MMP2 expression, as well as the increased Parkin level were also confirmed in in vivo experiments, further demonstrating the mechanisms responsible for the tumor-promoting effects of MMP11/14. Collectively, our study elucidated the role of MMP11 and MMP14 in the bidirectional crosstalk between adipocytes and CRPC cells and provided the rationale of targeting MMP11/14 for the treatment of CRPC patients.
Keywords: Castration resistant prostate cancer; adipocyte; lipid metabolism; matrix metalloproteinase; mitophagy.
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