Abstract
The L1 cell adhesion molecule (L1CAM) has been implicated in tumor progression of many types of cancers, but its role in prostate cancer and its application in targeted gene therapy have not been investigated. Herein, we demonstrated that the L1CAM was expressed in androgen-insensitive and highly metastatic human prostate cancer cell lines. The correlation between L1CAM expression and prostate cancer metastasis was also validated in serum samples of prostate cancer patients. Knockdown of L1CAM expression in prostate cancer cells by RNA interference significantly decreased their aggressive behaviors, including colony formation, migration and invasion in vitro, and tumor formation in a metastatic murine model. These anti-malignant phenotypes of L1CAM-knockdown cancer cells were accompanied by G0/G1 cell cycle arrest and suppression of matrix metalloproteinase (MMP)-2 and MMP-9 expression and nuclear factor NF-κB activation. In vivo targeting of L1CAM expression using liposome-encapsulated L1CAM siRNAs effectively inhibited prostate cancer growth in mouse bone, which was associated with decreased L1CAM expression and cell proliferation by tumor cells. These results provide the first evidence for L1CAM being a major contributor to prostate cancer metastasis and translational application of siRNA-based L1CAM-targeted therapy.
Highlights
Prostate cancer is the most frequently diagnosed cancer in men and the second leading cause of cancer deaths among men in the United States [1]
We focused on defining the role and specific mechanisms of L1 cell adhesion molecule (L1CAM)’s involvement in the disease progression of prostate cancer and investigating the feasibility and efficacy of using an RNA interference (RNAi) approach for the in vivo targeting of L1CAM expression for treating human prostate cancer bone metastasis
DU145 cells derived from metastatic lesions in the dura mater expressed lower levels of the L1CAM compared to PC3 cells, whereas androgen-dependent LNCaP with low metastatic potential and normal prostatic epithelial PrEC cells exhibited no L1CAM expression
Summary
Prostate cancer is the most frequently diagnosed cancer in men and the second leading cause of cancer deaths among men in the United States [1]. The most common site of prostate cancer metastasis is in bone, with skeletal metastases identified at autopsy in up to 90% of patient dying from the disease [2]. Skeletal metastasis results in significant complications including severe pain, pathological fractures and spinal cord compression, bone-metastasis-evoked cranial neuropathy from baseof-skull syndromes, anemia, and infection [3]. While localized prostate cancer can be cured, patients with bone metastasis and resulting complications often have www.impactjournals.com/oncotarget a poor prognosis and a median survival of 1~3 years [4]. Androgen deprivation therapy is the firstline therapy for metastatic prostate cancer. The disease often progresses to the androgen-independent bone-metastatic stage. Novel therapeutic approaches based on a mechanistic understanding of prostate cancer metastasis and survival in the bone are needed to further improve the prospects for survival of men with hormonerefractory prostate cancer metastasis
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