Prostate cancer has become the most frequently diagnosed neoplasm and the second leading cause of cancer-related mortality in men. Hormone refractory prostate cancer frequently relapses from therapy and inevitably progresses to bone-metastatic status with no cure; however, the molecular mechanisms underlying this event are poorly understood. Adhesion molecules mediate cell-cell and cell-matrix interactions and are essential for a variety of physiological and pathological processes including maintenance of normal tissue integrity as well as tumor development and progression. Consequently, modulation of adhesion molecules by radiation may have a role in radiation-induced tumor responses including cellular adhesion, metastasis, and survival. Understanding the interaction of radiation with adhesion molecules could have a major impact on developing new strategies to increase the efficacy of radiation therapy. We have previously demonstrated for the first time a strong correlation between the L1 cell adhesion molecule (L1CAM) expression and prostate cancer bone metastasis in serum samples of prostate cancer patients, as well as the oncogenic function of L1CAM in aggressiveness of prostate cancer cells. In the light of our preliminary findings that L1CAM expression was induced by oxidative stress such as radiation and its overexpression led to anti-apoptotic protection of androgen-independent prostate cancer cells from drug and ionizing radiation treatment, we imply that L1CAM is an oxidative stress-response gene contributing in therapeutic resistance of castration-resistant prostate cancer (CRPC). L1CAM has no intrinsic kinase activity for downstream signaling and L1CAM-mediated signaling has been largely attributed to an association with integrins or growth factor receptors through the interaction at cell surface. Phosphorylation of adhesion receptors regulated not only protein structure but also receptor interactions with cytosolic binding partners, including signaling and structural proteins. The cytoplasmic domain of L1CAM contains multiple potential phosphorylation sites. Thus, we hypothesize that phosphorylation of cytoplasmic domain of L1CAM contributes to mCRPC progression through intracellular interacting with critical signaling proteins that trigger a pro-metastatic and survival signal pathways. Targeting L1CAM intracellular signaling protein interaction therefore may lead to therapeutic cure of mCRPC. Specific Aim 1 will systematically analyze L1CAM phosphorylation at the cytoplasmic tail to assess whether they play a role in pro-metastatic function and to characterize the protein structure of intracellular domain of L1CAM to elucidate intracellular L1CAM-kinase interaction in three-dimensional space. Specific Aim 2 will further design and test novel therapeutic approach that is mediated by prostate cancer-specific cell permeable peptide-guided intracellular antibody to target this critical signaling pathway with a hope to “cure” prostate cancer bone metastasis. Specific Aim 3 will identify L1CAM-signaling noncoding RNAs and conduct a cohort study to assess its clinical significance in the prediction of mCRPC and therapy recurrence using liquid biopsy. Achievements of this proposal will not only provide key insights into the molecular basis of L1CAM intracellular signaling pathway, but also pave the way for potential new biomarker and treatment strategy for prostate cancer precision medicine.
|Effective start/end date||8/1/17 → 7/31/18|
- metastatic castration-resistant prostate cancer (mCRPC)
- cell adhesion molecule L1 (L1CAM)
- protein phosphorylation
- intracellular antibody
- liquid biopsy
- precision medicine