Research Profile
The overall objectives of my research are directed at understanding the molecular mechanism underlying the hormone insensitivity in advanced prostate cancer. Specifically, my research focuses 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 my laboratory.
We have recently 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, we also find that the direct interaction between AR and caveolin regulates a hormone-dependent cell motility and tumor cell invasion in prostate cancer. This is the first molecular evidence linking the hormonal signal to the promotion of tumor metastasis.
We have also identified a potential key regulator along this pathway, PAK6, a serine/ theronine protein kinase that had previously been identified as an AR interacting protein. We have determined that the interaction between PAK6 and AR is a mechanism that activates PAK6 kinase activity. Moreover, ectopic expression of constitutive active PAK6 kinase promotes prostate cancer cell anchorage independent tumor growth in soft agar assay. The intertwined relationships between these signal pathways suggest a cross-talk signal network at work. Our focus on dissecting these signals will undoubtedly contribute to our understanding of the mechanism of prostate cancer tumor metastasis. More importantly, novel drug targets may also be identified from these pathways.
Back to the top
Projects
1. Molecular Regulation of Androgen Receptor Activation.
Role: Principal Investigator
|
Caveolin, a scaffold protein associated with caveolae signaling microdomains, has been correlated with hormone resistance and metastasis in prostate cancer. We demonstrate in cellular models that modulations in caveolin levels dramatically alter the sensitivity of AR to androgen. Furthermore, a transient and dynamic direct interaction between AR and caveolin in response to androgen stimulation is also demonstrated. Our working hypothesis is that AR activation is potentially regulated by a cross-talk with signal complexes associated with caveolin containing caveolae. The current proposal is designed to rigorously evaluate the interaction between AR and caveolin-1 at molecular, cellular and physiological levels. The immediate goals are: (1) to define in detail the interaction between AR and caveolin-1 at molecular level, (2) to functionally characterize the interaction between AR and caveolin-1 in androgenic signaling, (3) to characterize the physiological role of caveolin overexpression in AR signaling using a prostate carcinoma cell culture model, and (4) to characterize the effect of caveolin-1 overexpression on LNCap cell tumorigenicity and metastasis using a nude mouse xenograft model. Fully characterizing the interaction between AR and caveolin can be extrapolated to the understanding of the pathobiology of prostate cancer progression as well as the normal prostate epithelial physiology of AR signaling. The long-term goals are to identify novel targets and mechanisms for future development of rational drug targets.
|
2. Gene Pathways of Tumor Cell Motility.
Role: Principal Investigator
| The goal of this project is to characterize the expression profiles and to identify pathway(s) that regulate(s) cell motility and invasive phenotypes in prostate cancer cells. Comparative analysis of gene expression profiles between non-metastatic and metastatic prostate cancers will facilitate the establishment of an annotated database of molecular profiles/pathways for cell motility/invasion related tumor metastasis. Cell motility and invasion are crucial aspects in metastatic spread of cancer. In view of the complex array of genetic factors contributing to tumor metastasis, DNA microarray is a powerful tool to examine the global response underlying the molecular mechanism of cancer metastasis. These analyses may ultimately enable the identification and utilization of signature expression profiles or pathways of metastatic tumors to predict response to drugs or therapeutics in cancer prevention or therapy. |
Back to the top
Funding
Back to the top
Recent Publications
For the latest articles by Dr. Michael Lu, please visit 
.
1. Lu ML, Schneider MC, Zhang X, Richie JP. Caveolin-1 interacts with androgen receptor: a positive modulator of androgen receptor mediated transactivation. J Biol Chem 2001; 276:13442-51.
2. Yuan X, Lu ML, Li T, Balk SP. SRY Interacts and Negatively Regulates Androgen Receptor Transactivational Activity. J Biol Chem 2001; 276:46647-54.
3. Lee SR, Ramos SM, Ko A, Masiello D, Swanson KD, Lu ML, Balk SP. Androgen and Estrogen Receptor Interaction with a Novel p21 Activated Kinase (PAK6). Mol Endocrin 2002; 16:85-99.
4. Zhuang L, Lin J, Lu ML, Solomon KR, Freeman MR. Cholesterol-rich lipid rafts mediate Akt-regulated cell survival in prostate cancer cells. Cancer Res. 2002; 62:2227-31.
5. Wilbur A, Lu ML, Schneider MC. Media Containing DNASE1L3, and not DNASE1, confers a barrier to liposomal transfection. Mol Therapy 2002; 6:35-42.
6. Zhang Y, Fondell,JD, Xia X, Wang Q, Cheng A, Lu ML, Hamburger AW. Repression of androgen receptor mediated transcription by the ErbB-3 binding protein, Ebp1. Oncogene 2002; 21:5609-18.
7. Masiello D, Cheng S, Bubley G, Lu ML, Balk SP. Bicalutamide functions as an androgen receptor antagonist by assembly of a transcriptionally inactive receptor. J Biol Chem 2002; 277:26321-6.
8. Shi G-P, Sukhova GK, Kuzuya M, Zhang Y, Pan J-H, Lu ML, Cheng XW, Iguchi A, Perrey S, Lee A M-E, Chapman HA, Libby P. Deficiency of The Cysteine Protease Cathepsin S Impairs Microvessel Growth. Circulation Res 2003; 92:493-500.
9. Sukhova1 GK, Zhang Y, Pan JH, Wada Y, Yamamoto T, Naito M, Kodama T, Tsimikas S, Witztum JL, Lu ML, Sakara1 Y, Chin MT, Libby P, Shi G-P. Deficiency of Cathepsin S Reduces Atherosclerosis In Low-Density Lipoprotein Receptor-Deficient Mice. J Clin Invest 2003; 111:897-906.
10. Wilbur A, O’Connor TP, Lu ML, Schneider MC. DNASE1L3 Deficiency in Lupus-prone MRL and NZB/W F1 Mice. Clin Exp Immunol 2003; 134:46-52.
11. Mukhopadhyay NK, Gilchrist D, Gordon GJ, Chen C-J, Bueno R, Lu ML, Salgia R, Sugarbaker DJ, Jaklitsh MT. Integrin Dependent Protein Tyrosine Phosphorylation is a Key Regulatory Event in Collagen IV Mediated Adhesion and Proliferation of Human Ling Tumor Cell Line, Calu-1. Thor. Surgery 2004; 78:450-457.
12. Kaur R, Liu X, Gjoerup O, Zhang A, Yuan X, Balk SP, Schneider MC, Lu ML. Activation of p21-activated kinase 6 by MAP kinase kinase 6 and p38 MAP kinase. J Biol Chem. 2005 Feb 4;280(5):3323-30. Epub 2004 Nov 18.
13. Jia Y, Liu KL, Zhou B, Lu ML, Liang WB, Zhang L. A multiplex for simultaneous amplification of three Y-STR loci using modified primers. Sichuan Da Xue Xue Bao Yi Xue Ban. 2005 Jan;36(1):17-9. Chinese.
14. Freeman MR, Cinar B, Lu ML. Membrane rafts as potential sites of nongenomic hormonal signaling in prostate cancer. Trends Endocrinol Metab. 2005 Jul 4
15. Mukhopadhyay NK, Gilchrist D, Gordon GJ, Chen CJ, Bueno R, Lu ML, Salgia R, Sugarbaker DJ, Jaklitsch MT. Integrin-dependent protein tyrosine phosphorylation is a key regulatory event in collagen-IV-mediated adhesion and proliferation of human lung tumor cell line, Calu-1. Ann Thorac Surg. 2004 Aug;78(2):450-7.
Back to the top
Send Feedback to: Department of Surgery Webmaster at bwhsurgery@partners.org
