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Li Lab
Li, Fengzhi, PhD
Associate Member/Associate Professor of Oncology
Department of Pharmacology and Therapeutics
Roswell Park Cancer Institute (RPCI)
Elm and Carlton Streets
Buffalo NY USA 14263
Tel: 716 - 845 - 4398/1565
Fax: 716 - 845 - 8857
E-mail: fengzhi.li@roswellpark.org
Program
Apoptotic and antiapoptotic genes; survivin; prostate derived Ets factor (PDEF); essential cancer-associated genes; transcriptional and epigenetic gene regulation; cell cycle control; gene targeting; chemotherapeutic drug resistance and action mechanism; drug discovery and development.
Proteins belonged to the inhibitor of apoptosis (IAP) family are one of the major research interests in this laboratory. Members in the IAP family were found in virus, yeast, nematode, fruit fly and mammal. All IAP family members share one or more signature motifs termed baculovirus IAP repeat (BIR) which consists of a conserved sequence of about 70 amino acids. Eight human IAP family members have been identified so far: c-IAP1, c-IAP2, XIAP, NAIP, survivin, apollon, ML-IAP/livin and ILP-2. Survivin appears to be a novel member in this family and has a number of distinct features that it does not share with other members in this family: 1) survivin is the smallest member and homodimerized in solution; 2) it is undetectable in normal, differentiated adult tissues but highly expressed in human cancers; 3) expression of survivin is cell cycle-regulated with a robust increase in G2/M phase; and 4) survivin appears to be localized in multiple unique subcellular locations, and consistently its function is involved in both inhibition of apoptosis and regulation of cell division while other IAP members are restricted to one of these two functions.
Dr. Li has been initially involved in characterization of the novel IAP member, survivin. He and his colleagues demonstrated that survivin controls a “default” apoptotic checkpoint during mitosis (Li et al., Nature, 396: 580-584, 1998), and that interference of survivin expression and function induces both programmed cell death (apoptosis) and cell division defects (Li et al., Nature, 396: 580-584, 1998; Li et al., Nat Cell Biol, 1: 461-466, 1999). He and his colleagues also initially found that the regulation of survivin is cell cycle-controlled with a robust expression at G2/M phase of the cell cycle (Li et al., Nature, 396: 580-584, 1998; Li et al., Cancer Res, 59: 3143-3151, 1999) and that Sp-1 appears to be one important factor for the constitutive expression of survivin in cancer cells (Li et al., Cancer Res, 59: 3143-3151, 1999; Li et al., Biochem J, 344: 305-311, 1999). The fact that survivin highly expresses in cancer but is undetectable in normal, differentiated adult tissues makes survivin be an excellent novel target for cancer therapeutics. Importantly, although our recent studies indicate that a few proliferative normal tissues express survivin, its expression, with the exception of testes, is very low and is only in far less than 5% of the total cells. More importantly, growing evidence indicates that although survivin plays a role in certain physiology, the regulation and/or functional mechanism of survivin in cancerous versus normal tissues and cells are likely different. Another important issue related to cancer therapeutics is the cancer initiation and prevention. It is known that abnormal inhibition of physiological apoptosis is a critical step for cancer initiation (carcinogenesis or tumorigenesis). Although the underlying mechanism is not fully understood, evidence indicates that survivin appears to play an important role in the initiation and progression of various human cancers, and PDEF exerts its tumor suppressor activity through inhibition of survivin expression. Therefore, survivin is not only an excellent novel target for cancer therapeutics but also an important biomarker and target for cancer diagnosis, prognosis and prevention.
Progress
The research efforts currently, as well as in the coming years, focus on the following four research areas in our laboratory:
* Drug discovery and development: Two approaches are used for the discovery and development of new anti-cancer drug candidates for therapeutic drug development: 1) Collaborating with chemists to synthesize small organic chemical compounds (MW<500) under computerized modeling for potentially disrupting the critical protein-protein or DNA-protein interactions. Compounds synthesized in this way are then tested for their biological functions and action mechanisms; and 2) we have developed high throughput screen (HTS)-compatible cell-based screening systems. We then collaborate with HTS facilities in academic institutions as well as Pharma/BioTech companies for candidate drug screening and development. This approach is also performed for 96-well plate-based drug screening in a lab-base scale.
* Transcriptional regulation of the antiapoptotic survivin gene and other essential tumor promoter/suppressor genes for cancer therapeutics: The available data suggest that survivin can be regulated by various stimuli including DNA damage, growth factors/cytokines, anticancer agents, hormones, viral protein, polyamine analogs and kinase inhibitors. We believe that controlling the expression of survivin and other essential tumor promoter/suppressor genes will ultimately control cancer progression and metastasis, and finally lead to cancer cell differentiation into normal cells or being engaged in apoptosis. We currently use the survivin and PDEF genes as model systems to delineate the molecular mechanism of transcriptional regulation in cancer cells toward our target for cancer therapeutics.
* Identification of protein factors associated with cancer cell proliferation and tumorigenesis: A number of interesting protein factors have been identified that interact with IAP proteins or regulatory regions of the survivin gene, which appear to be important for the modulation of cancer cell growth. In addition, we have located a novel protein factor by a unique phospho-specific antibody, which appears to be associated with cancer cell proliferation. All of these new protein factors will gradually become our focus in the coming years toward the application of these proteins as novel targets for cancer therapeutics.
* Molecular gene targeting and anticancer drug action mechanism: Based on the function and transcriptional regulation of the essential cancer-associated genes/proteins, we, in collaboration with other scientists in and outside of our institute, are engaged in the investigation of various antitumor drug resistance and action mechanisms, and trying to translate our current research into meaningful clinic applications for treatment of cancer.
Selected publications from 2004 to 2007
1. Ling X, Cheng QY, Black JD, Li F. Forced expression of survivin-2B abrogates mitotic cells and induces mitochondria-dependent apoptosis by blockade of tubulin polymerization and modulation of Bcl-2, Bax and survivin. J Biol Chem 282:27204-14, 2007.
2. Wu J, Apontes P, Song L, Liang P, Yang L, Li F. Molecular mechanism of upregulation of survivin transcription by the AT-rich DNA-binding antitumor agent, Hoechst33342: evidence for survivin involvement in drug resistance, Nucleic Acids Res., 35(7): 2390-402, 2007.
3. Ghadersohi A, Pan D, Fayazi Z, Hicks DG, Winston JS, Li F. Prostate-derived Ets transcription factor (PDEF)downregulates survivin expression and inhibits breast cancer cell growth in vitro and xenograft tumor formation in vivo. Breast Cancer Res Treat. 102: 19-30, 2007.
4. Spaulding B, Pan D, Ghadersohi A, Nielsen G, Jensen S, Gellert F, Ling X, Zhang M, Black A, Li F. Characterization of the 12C4 survivin monoclonal antibody and insight into the expression of survivin in human adult tissues. Histopathology, 49: 622-633, 2006.
5. Zhang M, Yang J, Li F. Transcriptional and post-transcriptional controls of survivin in cancer cells: Novel approaches for cancer treatment. J. Exp. Clin. Cancer Res., 25(3): 391-402, 2006.
6. Azrak RG, Frank CL, Ling X, Li F, Foster BA, Rustum YM. The mechanism of methylselenocysteine and docetaxel synergistic activity in prostate cancer cells. Mol Cancer Ther, 5(10): 2540-8, 2006.
7. Li F, Brattain MG. Role of the survivin gene in pathophysiology, American J of Pathology, 169(1): 1-11, 2006.
8. Li F, Ling X. Survivin study: an update of “what is the next wave?” Journal of Cellular Physiology, 208: 476-486, 2006.
9. Borbely AA, Murvai M, Konya J, Beck Z, Gergely L, Li F, Veress G. Effects of human papillomavirus type 16 oncoproteins on survivin gene expression. J Gen Virol 87:287-294, 2006.
11. Li F. Role of survivin in cancer chemoprevention, Assay Designs-Simply Science: Issue 1, page 2-6, 2005.
12. Li F. Chapter VI: Survivin, other IAPs, Smac/DIABLO, and Omi/HtrA2 – modulation of the advancing apoptotic process, in the book of “Apoptotic pathways as target for novel therapies in cancer and other diseases.” edited by M. Los & S.B Gibson; Kluwer Academic Press (ISBN: 0-387-23384-9), pp137-155, 2005.
13. Ling X, Yang J, Tan D, Ramnath N, Younis T, Bundy B, Slocum HK, Yang L, Zhou M, Li F. Differential expression of survivin-2B and survivin-DEx3) is inversely associated with disease relapse and patient survival in non-small-cell lung cancer (NSCLC). Lung Cancer, 49: 353-361, 2005.
14. Wu J, Ling X, Pan D, Apontes P, Song L, Liang P, Altieri DC, Beerman T, Li F. Molecular mechanism of inhibition of survivin transcription by the GC-rich sequence-selective DNA-binding antitumor agents, hedamycin: Evidence of survivin down-regulation associated with drug sensitivity, J Biol Chem., 280(10): 9745-9751, 2005.
15. Li F. Role of Survivin and its Splice Variants in Tumorigenesis. Br J Cancer, 92(2): 212-6, 2005.
16. Li F, Ling X, Huang H, Brattain L, Apontes P, Wu J, Binderup L, Brattain MG. Differential regulation of survivin expression and apoptosis by vitamin D3 in two isogenic MCF-7 breast cancer cell sublines. Oncogene, 24(8): 1385-95, 2005.
17. Li F, Yang J, Ramnath N, Javle MM, Tan D., Nuclear and/or cytoplasmic expression of survivin: What is the significance? Int J Cancer, 114(4): 509-12, 2005.
18. Zhu N, Gu L, Findley HW, Li F, Zhou M. An alternatively spliced survivin variant is positively regulated by p53 and sensitizes leukemia cells to chemotherapy. Oncogene, 23(45): 7545-51, 2004.
19. Javle MM, Tan D, Yu J, LeVea, CM, Li F, Kuvshinoff BW, Gibbs JF. Nuclear survivin expression predicts poor outcome in cholangiocarcinoma. Hepato-Gastroenterology 51(60): 1653-7, 2004.
20. Ling X, Bernacki RJ, Brattain MG, Li F. Induction of survivin expression by taxol (taxane paclitaxel) is an early event and is independent of taxol-mediated mitotic arrest. Journal of Biological Chemistry, 279(15): 15196-15203, 2004.
21. Yang L, Cao Z, Li F, Post DE, Van Meir EG, Zhong H, Wood WC. Tumor-specific gene expression using the survivin promoter is further increased by hypoxia. Gene Therapy, 11(15): 1215-23, 2004.
22. Ling X, Li F. Silencing of antiapoptotic survivin gene by multiple approaches of RNA interference technology. BioTechniques, 36(3): 450-460, 2004.
23. Zhu ZB, Makhija SK, Lu B, Wang M, Kaliberova L, Liu B, Rivera AA, Nettelbeck DM, Mahasreshti PJ, Leath CA, Barker S, Yamaoto M, Li F, Alvarez RD, Curiel DT. Transcriptional Targeting of Tumors with a Novel Tumor-Specific Survivin Promoter. Cancer Gene Therapy,11(4): 256-62,2004.
