Implications of metabolic reprogramming in vascular and cancer biology

Vascular diseases and cancer are the major causes of mortality world-wide. Although a significant progress has been made in diagnosis and treatment of cancer and several vasculopathies, our knowledge of the mechanism(s) causing these diseases is still incomplete and therefore treatments are inadequate. Metabolic reprogramming “Warburg Phenomenon” is a hallmark of cancer and vascular diseases. Seminal studies from our laboratory have contributed to establish the role of increased glucose-6-phosphate dehydrogenase (G6PD) or activation of the pentose phosphate pathway (PPP) in the pathogenesis of pulmonary arterial hypertension – a cancer like vascular disease, and in oncogenesis. Therefore, long-term goals of our laboratory are to develop: 1) knowledge how metabolic reprogramming activates maladaptive gene expression in the cell leading to vascular diseases and cancer, and 2) novel treatments targeting G6PD to reverse metabolic reprogramming and to inhibit and reverse vascular diseases and tumor growth. Using the state-of-the-art bioengineering approaches like 2D-echocardiography, computer tomography, cardiac catheterization (which measures hemodynamic changes), wire and pressure myography, AFM, and variety of other modern approaches, including CRISPR-Cas9 editing, our laboratory has gained a significant insight regarding the role of G6PD in vascular and cancer pathology. In addition to this, our laboratory is also investigating the role of G6PD in eliciting metabolic reprogramming and DNA as well as histone modifications (methylation and acetylation) that contributes to the development of vascular diseases, including pulmonary arterial hypertension, triple negative breast cancer (TNBC), and lung carcinoma. Recently, we have initiated a new program to develop organ-on-chip studies to determine the role of G6PD-driven communication between the lung and hematopoietic stem cells in the progression of pulmonary and vascular fibrosis, hypertension, and carcinoma.  Our results demonstrate that inhibition of G6PD activity decreased glucose metabolism through the PPP, prevented Warburg metabolism, stopped cell migration, and evoked death, of TNBC (MDA-MB-231) cells. Furthermore, inhibition of G6PD activity reversed pulmonary arterial hypertension and arterial fibrosis/stiffness. These findings suggest that G6PD acts as a link between reprogrammed metabolism and aberrant gene regulation and plays a crucial role in regulating the phenotype of cells implicated in the pathogenesis of vascular diseases and cancer.

Dr. Gupte is a Professor and Director of Graduate Program of Pharmacology at New York Medical College. He graduated from Juntendo School of Medicine, Tokyo, Japan, and did his post-doctoral fellowship at New York Medical College, NY, USA. Here he was promoted to Professor of Pharmacology. His work led to paradigm shifting discoveries in nitric oxide and vascular biology and has established the significance of glucose-6-phosphate dehydrogenase and metabolic reprogramming in regulating cardiovascular hemodynamics, vascular remodeling, and arterial stiffness. Seminal studies from his laboratory later led to the drug discoveries in vascular and cancer biology. He is nationally and internationally recognized for his work in vascular and pulmonary medicine. Dr. Gupte has expertise in several state-of-the-art techniques like 2D-echocardiography, ultrasound, computer tomography, atomic force microscopy and beyond that are applied in the study of cardiovascular hemodynamics. Also, he has expertise in drug discovery and pharmaceutical sciences including nanoparticle technology used for targeted drug delivery. His research program is funded by AHA and NIH-NHLBI. Dr. Gupte has published 80 peer-reviewed journal articles, 13 invited review papers, 3 invited editorials, 6 book chapters, and 2 patents. He is regularly invited as a speaker nationally and internationally. Frequently, he is invited to be on NIH-regular and PPG study sections, and to review grants by foreign governments and agencies. He has previously served as a member and chair of AHA-Vascular Biology study section. He is on the editorial board of American Journal of Physiology-Heart and Circulation and Vascular Pharmacology, and Associate Editor of Frontiers in Physiology-metabolism. Dr. Gupte has trained 9 post-doc fellows (MDs, and PhDs) and 7 PhD students, who went on be either faculty members at universities or to be leaders in the industry. Besides, several medical, graduate, college, and high school students were trained in his laboratory. Many of his students have received awards for excellence in research at regional and state levels. Dr. Gupte is a recipient of several fellowships and awards including Cournand & Comroe Young Investigator Prize (AHA), Young Investigator Award from Indian Association of Cardiovascular and Thoracic Surgeons, Fulbright Research Award to host International Scholar from Ukraine, Monbusho scholarship, fellowship from Association of International Education in Japan, International Travel Award from International Society for Heart Research and Japanese Circulation Society, and Dean’s Excellence in Research Award.