Charles E. Schmidt College of Medicine
Florida Atlantic University
777 Glades Road, BC-71
Boca Raton, FL 33431
The overall objective of Dr. Lu’s research is directed at understanding the molecular mechanism underlying the hormone insensitivity in advanced prostate cancer progression. Specifically, the focus is on characterizing the molecular regulation of androgen receptor (AR) signal pathways. The emergence of hormone-independent prostate cancer curtails the effectiveness of hormonal therapies. One mechanism for prostate cancer cells to circumvent the hormonal therapy is to introduce/select mutant androgen receptors (AR) that eventually turn an antagonist into an agonist as evident both in vivo and in vitro. However, these mutational changes of AR only appear in a small subset of late stage tumors. The search for other perturbations such as altered cellular signal transduction pathways leading to hormone independent AR activation is being pursued intensely in the laboratory.
The lab previously identified a novel mechanism that links AR activation to a major cytoplasmic signaling caveolin-complex. The demonstration of caveolin-1 modulating AR transactivation provides new insights into how the cross-talk between hormone actions and cellular signals regulates prostate cancer progression. Furthermore, it was found that the direct interaction between AR and caveolin containing raft domain regulates a hormone dependent cell motility and tumor cell invasion in prostate cancer. This is the first molecular evidence linking the plasma membrane component-regulated hormonal signal to the promotion of tumor progression and metastasis.
More recently, the lab has focused on studying a newly identified potential key regulator PAK6 (p21 Activate Protein Kinase 6) along this pathway. PAK6 was previously determined to be an AR interacting protein. PAK6 was determined to be overexpressed in advanced prostate cancer. Ectopic expression of constitutive active PAK6 kinase promotes prostate cancer cell motility and anchorage independent cell growth. Moreover, recent results also indicate PAK6 play a pivotal role in maintaining cellular proteostasis. The intertwined relationships between these signal pathways suggest a cross-talk signaling network at work. Dissecting these signals will undoubtedly contribute to the understanding of the mechanism of prostate cancer tumor progression and metastasis. More importantly, novel drug targets may also be identified from these pathways.