Tumor Signaling and Angiogenesis


Wendy B. Bollag, PhD, FAHA

Wendy B. Bollag, PhD, FAHA

Member,  Tumor Signaling and Angiogenesis
Professor of Physiology, Oral Biology, Graduate Studies, Cellular Biology and Anatomy, Medicine (Dermatology) and Orthopedic Surgery

 

 

 

Georgia Cancer Center
1467 Laney Walker Blvd., CA-1008
Office: 706-721-0698
Lab: 706-721-0704
E-mail: wbollag@augusta.edu

Research Summary

My laboratory is interested in the signals that regulate normal cell processes and what goes wrong in cancer, with the idea that prevention of cancer may be as effective, or perhaps even more effective, than treatment of the disease. In particular, I study the signaling mechanisms that regulate the growth (proliferation) and maturation (differentiation) of epidermal keratinocytes, the primary cell constituents of the outer layer of the skin, the epidermis. Keratinocytes can transform into the non-melanoma skin cancers, which are the most common cancers in the world, with approximately three million new cases diagnosed each year in the United States alone. While most non-melanoma skin cancers are remedied by surgical removal, treatment is often disfiguring as these cancers occur mostly on visible skin. My laboratory has identified one signal that promotes keratinocyte growth, maturation and survival while another signaling pathway that we study inhibits growth and promotes maturation, and both are abnormal in non-melanoma skin cancers.  

Research Interests

Protein Kinase D in Epidermal Keratinocyte Proliferation, Differentiation, Survival and Tumorigenesis
My laboratory investigates the signaling mechanisms that regulate the proliferation and differentiation of epidermal keratinocytes and the role of these mechanisms in the development of non-melanoma skin cancers. The etiology of the non-melanoma skin cancers is not entirely understood, although the most important risk factor for these cancers is chronic sun exposure, that is, ultraviolet (UV) radiation. We are studying the involvement of protein kinase D in promoting keratinocyte proliferation and survival and inhibiting differentiation. We previously showed that protein kinase D levels are increased in the non-melanoma skin cancer basal cell carcinoma, that protein kinase D is activated by UV irradiation of epidermal keratinocytes and that this activated protein kinase D protects keratinocytes from UV-induced cell death (apoptosis). Thus, our results provide a potential link between protein kinase D, sun-induced non-melanoma skin cancers and epidermal tumorigenesis. We are currently examining the mechanism by which protein kinase D protects keratinocytes from UV-induced apoptosis.

The Phospholipase D2-Aquaporin-3 Signaling Module in Epidermal Keratinocyte Proliferation, Differentiation and Tumorigenesis

On the other side of the equation, my laboratory has also found evidence of the involvement of another pathway in inhibiting keratinocyte proliferation and stimulating differentiation. This pathway is composed of the lipid-metabolizing ezyme phospholipase D2 (PLD2) and the glycerol transporter aquaporin-3 (AQP3). PLD2 is able to convert the glycerol transported by AQP3 into the lipid signal phosphatidylglycerol (PG), which can regulate keratinocyte growth and maturation. Furthermore, the levels of AQP3 and/or PLD2 are abnormal in the non-melanoma skin cancers, suggesting a potential role in cancer development in the skin. AQP3 may also be involved in the skin disease psoriasis, which is characterized by excessive (non-cancerous) proliferation of keratinocytes, abnormal keratinocyte differentiation and skin inflammation. In both cases we are investigating the regulation of the pathway components as well as the mechanisms by which these factors act to regulate keratinocyte and skin function

Other Areas of Interest

Finally, my laboratory collaborates with a number of other laboratories to understand the cell signaling mechanisms that regulate various other cell processes, including breast, prostate and metastatic colon cancer cell proliferation and/or cell death (apoptosis), as well as hormone secretion, bone formation and corneal epithelial wound healing.

Selected Publications

  1. Arun SN, D Xie, ME Dodd, X Zhong & WB Bollag. The potential use of protein kinase D inhibitors for prevention/treatment of epidermal tumors. J. Dermatol. Sci., 60: 29-39, 2010.
  2. Arun SN, I Kaddour-Djebbar, BA Shapiro & WB Bollag. UVB-induced activation of protein kinase D protects mouse keratinocytes from apoptosis. Oncogene, 30: 1586-1596, 2011 (e-published ahead of print Dec 6, 2010).
  3. Voss K, RJ Bollag, N Fussell, C By, DJ Sheehan & WB Bollag. Abnormal aquaporin-3 protein expression in hyperproliferative skin disorders. Arch. Dermatol. Res., 303: 591-600, 2011 (e-published ahead of print Mar 13, 2011).
  4. Choudhary V, I Kaddour-Djebbar, V Lakshmikanthan, T Ghazaly, G-S Thangjam, A Sreekumar, RW Lewis, IG Mills, WB Bollag & MV Kumar. Novel role of androgens in mitochondrial fission and apoptosis. Mol. Cancer Res., 9: 1067-1077, 2011 (e-published ahead of print, Jul 1, 2011).
  5. Liu F-y, Q-q Liu, D Yang, WB Bollag, K Robertson, P Wu & K Liu. Verticillin A overcomes apoptosis resistance in human colon carcinoma through DNA demethylation-dependent up-regulation of BNIP3. Cancer Res., 71: 6807-6816, 2011 (e-published ahead of print, Sep 12, 2011).
  6. Kaddour-Djebbar I, V Choudhary, V Lakshmikanthan, R Shirley, M El Gaish, M Al-Shabrawey, B Al-Husein, R Zhong, M Davis, Z Dong, WB Bollag & MV Kumar. Diltiazem enhances the apoptotic effects of proteasome inhibitors to induce prostate cancer cell death. J. Pharmacol. Exper. Ther., 341: 646-55, 2012 (e-published ahead of print, Mar 5, 2012).
  7. Xie D, M Seremwe, JG Edwards, R Podolsky & WB Bollag. Distinct effects of phosphatidylglycerol species on mouse keratinocye proliferation. PLoS One, 9: e107119, 2014.
  8. Choudhary V, LO Olala, H Qin, I Helwa, Z-q Pan, Y-Y Tsai, MA Frohman, I Kaddour-Djebbar & WB Bollag. Aquaporin-3 re-expression induced differentiation in a phospholipase D2-dependent manner in aquaporin-3 knockout mouse keratinocytes, J. Invest. Dermatol., 135: 499-597, 2015 (e-published ahead of print September 18, 2014).
  9. Choudhary V, LO Olala, I Kaddour-Djebbar, I Helwa & WB Bollag. Protein kinase D1 deficiency promotes differentiation in epidermal keratinocytes, J. Dermatol. Sci., 76: 186-195, 2014 (e-published ahead of print October 2, 2014).
  10. Jain A, A Samykutty, C Jackson, D Browning, WB Bollag, M Thangaraju, S Takahashi & SR Singh. Curcumin inhibits PhIP-induced cytotoxicity in breast epithelial cells through multiple molecular targets. Cancer Lett., 365: 122-131, 2015 (e-published ahead of print May 21, 2015).
  11. Paschall AV, D Yang, C Lu, J-H Choi, X Li, F Liu, M Figueroa, NH Oberlies, C Pearce, WB Bollag, A Nayak-Kapoor & K Liu. Verticillin A is a selective histone methyltransferase (HMTase) inhibitor for SUV39H1, SUV39H2, G9a and GLP, J. Immunol., 195: 1868-1882, 2015 (e-published ahead of print July 1, 2015).
  12. Choudhary V, LO Olala, K Kagha, Z-q Pan, X Chen, R Yang, A Cline, I Helwa, L Marshall, I Kaddour-Djebbar, M McGee-Lawrence & WB Bollag. Regulation of the glycerol transporter, aquaporin-3, by histone deacetylase-3 and p53 in keratinocytes. J. Invest. Dermatol., e-published ahead of print May 16, 2017.

  Awards

  • Outstanding Faculty Award, Medical College of Georgia, School of Graduate Studies, 2006
  • Outstanding Performance Award, Charlie Norwood VA Medical Center, annually 2008-present
  • Distinguished Service Award, Medical College of Georgia, School of Graduate Studies, 2009
  • Distinguished Research Award, Medical College of Georgia, School of Graduate Studies, 2010
  • VA Research Career Scientist Award, 2011-2016
  • Nomination and selection as a Fellow of the American Heart Association, 2011
  • Distinguished Faculty Award, Basic Science Research, Georgia Health Sciences University, Medical College of Georgia (School of Medicine), 2012
  • Distinguished Teaching Award, Georgia Regents University, The Graduate School, 2013
  • Nomination to and selection as a participant in the GRU Executive Leadership Excellence Program, 2014-2015
  • MCG Exemplary Teaching Award, Medical College of Georgia at Augusta University, 2016

Current Funding

VA Merit                                              Bollag (PI)                        07/01/16-06/30/20
Veterans Administration                                                              6 calendar months
“Epidermal Aquaporin-3 in Psoriasis”
The aim of this award is to determine the role of aquaporin-3 in psoriasis and the effect of aquaporin-3-transported glycerol in this disease.

P01 AG27175                                     Isales (PI)                          04/15/17-03/31/22
NIH/NIA                                                                                       1.2 calendar months
“Age-induced Impairment of Nutrient Signaling Results in Bone Loss”             
The aim of this program project is to determine the role of nutrients in regulating bone formation by mesenchymal stem cells and osteoblasts and the decrease observed with aging.
Role: Co-Investigator on Project #1

Patents

  1.  U.S. Application No. 11/791,388 (the National Stage of International Application No. PCT/US2005/042748) “Phosphatidylglycerol Liposomes Normalize Keratinocyte Proliferation” -- U.S. Provisional Application No. 60/635,565 filed November 23, 2004 and full application filed November 23, 2005; Continuation-in-Part “Methods and Compositions for Modulating Keratinocyte Function” filed June 28, 2008 as U.S. Application No. 12/164,021. U.S. Patent No. 8,808,715 awarded August 19, 2014.
  2. U.S. Application No. 13/068,007 “Ocular Compositions Containing Dioleoylphosphatidyl-glycerol and Uses Thereof” -- U.S. Provisional Application No. 61/343,449 filed April 29, 2010 and full application filed April 29, 2011.  U.S. Patent No. 8,524,692 awarded September 3, 2013.

Research team

photo of Sara Chen, MD
Sara Chen, MD

Research Assistant & Laboratory Manager
photo of Vivek Choudhary, DVM, PhD 
Vivek Choudhary, DVM, PhD 

Assistant Research Scientist 
photo of Purnima Merai, MS 
Purnima Merai, MS 

Part-time Research Assistant 
photo of Ismail Kaddour-Djebbar, MD 
Ismail Kaddour-Djebbar, MD 

Adjunct Postdoctoral Fellow and VA Laboratory Manager 
photo of Rawipan Uaratanawong, MD 
Rawipan Uaratanawong, MD 

Visiting Scholar