Research

Cancer Mitochondrial biology

Mitochondria is critical regulatory nodal points intersecting multiple cell death signaling pathways. We are interested in molecular regulatory mechanisms of mitochondrial outer and inner membrane permeabilization (MMP) which is the most important event for 'life or death' decision and is the 'point of no return' in cell death program. Mitochondrial chaperones and related molecules (Hsp90, TRAP1, Hsp60, mtHsp70, and Cyclophilin-D) and Bcl-2 family members regulate the mitochondrial membrane permeabilization and can induce biochemical, physiological, and structural changes in mitochondria. The function of these molecules in MMP and molecular mechansims of their cross-regulation are our primary interest.

(Figure) Mitochondria in cell death. Mitochondrial outer and inner membrane permeabilization is regulated by Bcl-2 family member proteins (MOMP) and permeability transition pore complex (MPT), respectively. MMP eventually leads to release of proapoptotic mitochondrial proteins into the cytosol, which is the point of no return in cell death program. Regulation of MMP is compromised in most cancer cells. (Mol. Aspects Med 31, 1 (2010))

TRAP1 functions in the mitochondria of glioma cancer stem cells

Glioblastoma (GBM) cancer stem cells (CSC) are primarily responsible for metastatic dissemination, resistance to therapy, and relapse of GBM, the most common and aggressive brain tumor. Development and maintenance of CSC require orchestrated metabolic rewiring and metabolic adaptation to a changing microenvironment. We showed that cooperative interplay between the mitochondrial chaperone TRAP1 and the major mitochondria deacetylase sirtuin-3 (SIRT3) in glioma stem cells (GSC) increases mitochondrial respiratory capacity and reduces production of reactive oxygen species. This metabolic regulation endowed GSC with metabolic plasticity, facilitated adaptation to stress (particularly reduced nutrient supply), and maintained "stemness." Inactivation of TRAP1 or SIRT3 compromised their interdependent regulatory mechanisms, leading to metabolic alterations, loss of stemness, and suppression of tumor formation by GSC in vivo. Thus, targeting the metabolic mechanisms regulating interplay between TRAP1 and SIRT3 may provide a novel therapeutic option for intractable GBM patients.

Development of mitochondria-targeted drugs to treat cancer 

Most cancers develop inhibitory mechanisms against the induction of MMP. We believe that small molecule chemical compounds interfering cancer mitochondrial death signaling pathways can be effective therapeutics to treat cancers. Through multidisciplinary research collaboration including in silico drug development and medicinal chemistry groups, we will develop novel cancer mitochondriotoxic reagents activating mitochondrial death signaling pathways specifically in cancer cells.

(Figure) Series of anticancer drugs developed and investigated by PI. All these drugs are mitochondriotropic, i.e. targeted to and accumulated in mitochondria, and induce mitochondrial membrane permeabilization through inhibiting mitochondrial chaperones followed by reactivation of Cyp-D, the MMP inducer of the mitochondrial inner membrane. (J. Clin. Invest. 119, 454 (2009); Cell 131, 257 (2007))

Development of TRAP1 inhibitors as cancer therapeutics

Tumors often overexpress mitochondrial chaperone TRAP1 which is closely related to the poor prognosis of cancer patients. We have developed two different classes of lead compounds targeting mitochondrial TRAP1 with a different mode of action of drug: SMTINs and Panvotinibs. TRAP1 inhibitors are conjugated with the mitochondrial targeting moiety, triphenylphosphonium, to afford SMTINs which efficiently accumulate inside mitochondria. Panvotinibs are mitochondria-permeable Hsp90 inhibitors inactivating Hsp90 and Grp94 as well as TRAP1. The simultaneous inactivation of all the Hsp90 family proteins by Panvotinibs dramatically augment cancer-specific cytotoxic activity. Currently, we are optimizing SMTINs and Panvotinibs to improve DMPK properties of the drugs.

Related interview: KDDF interview