Volunteer Faculty, Department of Molecular and Cellular Biology
Roswell Park Cancer Institute
Elm and Carlton Streets
Buffalo New York USA 14263
Tel: 716-845-3261
Fax: 716-845-8906
E-mail: charles.wenner@roswellpark.org

Education
BA, Chemistry, Temple University, College of Liberal Arts & Sciences, Philadelphia PA, 1948
PhD, Chemistry/Biochemistry, Temple University, Philadelphia PA, 1953

Description of Research

The long-term goal of our program is to understand the mechanism(s) by which cellular signaling networks act and how these pathways can be exploited for cancer therapy.   The combined use of strategies which consider the use of inhibitors of signal transduction pathways such as Ras, Raf and Akt and their inter-relations with second messengers and interference with the energetic pathways of the tumor tissue represent appealing targets for cancer therapeutics.    Since mitochondria act as primary or secondary targets for many therapeutically applied drugs, it is proposed that mitochondria offer a feasible target for inducing death of malignant cells.  Understanding of how factors which contribute to the binding of Hexokinase II to mitochondria offers an attractive way to potentiate the effectiveness of conventional chemotherapeutic agents.  .Recent reports demonstrate that Akt mediates the binding of Hexokinase II by negatively regulating the activity of glycogen synthetase kinase.    Upon inhibition of Akt, glycogen synthetase kinase is activated and hexokinase II is unable to bind to mitochondria.  This inhibition of Akt potentiates chemotherapeutic-induced cytotoxicity. 

 

In addition to utilizing detachment of hexokinase from mitochondria for promoting apoptosis of tumor cells, another approach that is worthy of study is the use of inhibitors of mitochondrial hexolinase catalytic activity.  Dysregulated cellular energy metabolism in cancer cells via effects on hexokinase compartmentation and activity offers renewed promise for therapy.

 

The program is also concerned with understanding the mechanism by which transforming growth factors such as TGF-ß1 alter signal transduction pathways by which increased invasiveness of tumors can occur. Recent evidence indicates that TGF- 1 can induce conversion of progressively malignant epithelial cells to fibroblastoid-like cells and changes in responsiveness to TGF-ß1 such that TGF-ß1 induces proliferative effects instead of inhibitory effects. This implies that TGF-ß1 can act as a regulatory switch and the study of its effects on the mechanisms of signal transduction pathways is critical to applications of diagnosis and therapy.  Thus, TGF-ß1 can have both positive and negative effects on tumorigenesis, acting early as a tumor suppressor, but later as a stimulator of tumor invasion. The latter may be clinically more significant since many human tumors over express TGF-ß. Therefore, the understanding of the mechanism of TGF-ß1 signaling may provide useful approaches to tumor therapy.

 

We have obtained evidence that TGF-ß1 interference with MAP kinase activation provides a mechanism for collaborative interactions between transcription factors involved in cyclin D1 expression. The contribution of cdk inhibitors relative to that of cyclin D1 1 must also be taken into consideration by which the TGF-ß regulatory switch sets a threshold for either cell cycle progression or inhibition. Our studies focus on attempting to learn the molecular mechanism of TGF-ß1 induced signaling, and to discover the critical point(s) of convergence that the TGF-ß1 pathway(s) interacts with other mitogen-induced pathways, particularly those mediated by tyrosine kinase receptors.

 

Summary

Progress in the understanding of mitochondrial membrane permeability and its regulation should allow one to integrate the process of apoptosis into cell physiology and facilitate the development of combinatorial enhancers of apoptosis and survival of tumor cells.

 

Selected Publications:

• Giordano A, Rustum Y, Wenner CE.  Cell Cycle: Molecular targets for diagnosis and therapy-tumor suppressor genes and cell cycle progression in cancer.  J Cell Biochem 70:1-7, 1998.
• Wenner CE, Yan S.  Perturbation of EGF-induced MAP kinase activation by TGF-beta1.  Brazilian J Med Biol Res 32:821-825, 1999. 
• Yan S, Krebs S, Leister KJ, Wenner CE.  Perturbation of EGF-activated MEK1 and PKB signal pathways by TGF-beta1 correlates with perturbation of EGF-induced cyclin D1 and DNA synthesis by TGF-beta1 in C3H 10T1/2 cells.  J Cell Physiol 185:107-116, 2000. 
• Chen JY, Leister KJ, Wenner CE.  Differential density responses of embryonic fibroblast.  In Vitro Cell Dev Biol Anim 37:263-265, 2001. 
• Yan S, Wenner CE.  Modulation of cyclin D1 and its signaling components by the phorbol ester TPA and the tyrosine phosphatase inhibitor vanadate.  J Cell Physiol 186:338-349, 2001. 
• Wenner CE, Yan S.  Biphasic role of transforming growth factor beta in signal transduction and crosstalk.  J Cell Physiol 196:42-50, 2003.