News & Events
Find a Person
Publishing Page Side Content
John S. Colter Lectureship
William A. Bridger Lectureships in Biochemistry
Student Services Contact Information
How To Apply
Graduate Student Services Contact Information
Ing Swie Goping
Our Disease Focused Research
University of Alberta Links
Biochemistry Safety Links
Our Disease Focused Research
Ph.D, D.Sc., University of Birmingham
Department of Biochemistry
Faculty of Medicine & Dentistry
University of Alberta
357 Heritage Medical Research Center
Edmonton, Alberta, Canada
Lab Tel: 780.492.4613
Our work focuses on understanding how changes in signal transduction processes lead to increased progression of tumours, their spread (metastasis) and the development of resistance to chemotherapy and radiotherapy.
These are some of the most outstanding problems in successfully treating most types of cancer.
Our group focuses on messengers, which are produced by agonists that activate cell surface receptors. For example, we have a major interest in the enzyme, autotaxin, which is an important component in wound healing.
This is because autotaxin produces a bioactive compound called lysophosphatidate (LPA), which activates six G-protein coupled receptors. These receptors stimulate the migration, proliferation and survival of cells in the wounded area and they increase the development of a new blood supply
These functions of autotaxin and LPA are hijacked by tumours, which are likened to “wounds that do not heal”.
We showed that LPA signalling is part of a vicious cycle of inflammation in cancer in which LPA stimulus the production of at least 20 inflammatory cytokines and chemokines
These inflammatory mediators stimulate further autotaxin secretion and perpetuate the vicious cycle. This inflammatory milieu stimulates the tumour growth and metastasis.
We also discovered that LPA increases resistance to cancer treatment by decreasing the effectiveness of various chemotherapeutic agents (Taxol, doxorubicin, tamoxifen), which normally kill cancer cells. This is partly explained since we showed that LPA increases the stability of the transcription factor, Nrf2
. This activates the anti-oxidant response element, which increases the expression of proteins that protect cancer cells from oxidative damage caused chemotherapeutic agents. In addition, Nrf2 increase the transcription of the multidrug resistance proteins, which export both toxic oxidation products and chemotherapeutic drugs from cancer cells
Our work concentrates on blocking the autotaxin-LPA-inflammatory axis as a new strategy to improve cancer treatment. Most of our work so far has been with a long acting autotaxin inhibitor, which decreases LPA production and signalling. It also has a potent anti-inflammatory effect. Autotaxin inhibition decreases tumor growth, metastasis and it synergistic improves the efficacy of doxorubicin treatment
Another part of our work focuses on a family of three lipid phosphate phosphatases (LPPs), which destroy extracellular LPA and block its effects on cell signalling.
Expressions of LPP1 and LPP3 are decreased in many cancer cells and this amplifies the effects of LPA. We showed that restoring the low activity of LPP1 in cancer cells decreases tumour growth and metastasis by about 80%.
Conversely, the activity of LPP2 is increased in cancer cells and this is part of the transformed phenotype. Our work is now directed to devising strategies for increasing the expression of LPP1 and LPP3 relative to LPP2 as a new paradigm for blocking tumour growth and metastasis.
Our research group is integrated with that of Dr. Todd McMullen who is an Endocrine Surgeon in the Department of Surgery at the University of Alberta. We are now working jointly to translate our work on blocking the autotaxin-LPA-inflammatory axis into clinical practice as a new paradigm to improve the effectiveness of chemotherapy and radiotherapy.
Xiaoyun Tang, Research Associate
Zelei Yang, Graduate Student
Autotaxin in the crosshairs: Taking aim at cancer and other inflammatory conditions.
MGK Benesch, YM Ko, TPW McMullen and DN Brindley.
588 (2014) 2712-2727.
Regulation of autotaxin expression and secretion by lysophosphatidate and sphingosine1-phosphate.
TPW McMullen and DN Brindley
J Lipid Res.
J Lipid Res. in
Tumor-induced inflammation in mammary adipose tissue stimulates a vicious cycle of autotaxin expression and breast cancer progression.
MGK Benesch, X Tang,
J Dewald, W-F Dong, JR Mackey, DG Hemmings, TPW McMullen and DN Brindley. FASEB J, in press.
Autotaxin is an inflammatory mediator and therapeutic target in thyroid cancer.
J Dewald, A Lopez-Campistrous, YY Zhao, R Lai, JM Curtis, DN Brindley
and TPW McMullen. Endocrine-Related Cancer, in press
Inhibition of autotaxin delays breast tumor growth and lung metastasis in mice. M Benesch, X Tang, T Maeda, A Ohata, Y Zhao, B Kok, J Dewald, M Hitt, J Curtis, T McMullen and DN Brindley, FASEB J. 28 (2014)
stabilizes Nrf2 and increases the expression of genes involved in drug resistance and oxidative stress responses: Implications for cancer treatment.
G Venkatraman, MGK Benesch, X Tang, J Dewald, TPW McMullen &
29 (2015) 772-785.
Lipid phosphate phosphatase-1 expression in cancer cells attenuates tumor growth and metastasis in mice.
X Tang, MGK Benesch, J Dewald, YY Zhao,
N Patwardhan, WL Santos
, JM Curtis, TPW and DN Brindley. J Lipid Res. 55 (2014)
Email & Apps
University of Alberta