Projects
I. Oxidative-Stress Defense Programs in Cancer (Cancer Biology)
While there has been a public perception for decades that antioxidants prevent tumor initiation and progression, recent large-scale clinical trials have disproved this notion. Not only have these trials demonstrated that antioxidants failed to prevent cancer, but also that antioxidant supplementation can promote cancer incidence (Klein et al., JAMA 2011&2012). There is now highly compelling evidence that oxidative-stress defense programs are critically involved in tumor progression and resistance to numerous therapies, including chemotherapy, hormone therapies, and targeted therapies, and that antioxidants represent an ‘Achilles’ heel’ or vulnerability of tumor cells. However, the mechanisms by which cancer cells adapt to harsh oxidative stress conditions remain elusive.
Three-dimensional (3D) spheroid models recapitulate in vivo morphologies, such as cell polarization, organization of cell layers, and interactions with extracellular matrix (ECM), to regulate proliferation and survival. Survival of normal epithelial cells in 3D culture is dependent on attachment to ECM – inner cells, lacking ECM attachment, undergo both apoptotic and non-apoptotic cell death, generating a hollow lumen. Zach and Joan have previously shown that the death of centrally localized, matrix-deprived cells is preceded by an elevation in ROS levels due to metabolic alterations and that treatment of spheroids with exogenous antioxidants is sufficient to reduce this cell death (Schafer et al., Nature 2009). Tumor cells, on the other hand, are able to survive in the high oxidative stress inner spheroid space, raising the possibility that tumor cells upregulate oxidative-stress defense programs to prevent inner clearance in spheroids. Thus, 3D tissue culture is a feasible model to uncover the molecular mechanisms underlying oxidative-stress defense programs in cancer cells.
Nobuaki Takahashi Research Group utilizes 3D spheroid models coupled with CRISPR screening, chemical screening, and bioinformatics analysis of patient data and investigate a mechanism how cancer cells are able to evade apoptotic and non-apoptotic cell death upon oxidative stress.
[Publications]
1. Takahashi N* et al Molecular Cell 2020
2. Harris IS et al Cell Metabolism 2019
3. Takahashi N et al Cancer Cell 2018
II. Oxidative Stress and Hypoxia Sensing mechanisms in the body (Physiology, Pathology, and Evolutionary Biology)
Among Ca2+-permeable cation channels, transient receptor potential (TRP) channels have been attracted attention as unique sensors of a wide variety of stress stimuli. We have identified a class of TRP channels as a sensor of changes in cellular redox status. The TRPM2 channel was the first redox sensitive TRP channel to be identified among TRP channels – the channel is activated by H2O2 through the production of nicotinamide adenine dinucleotide and its metabolites, ADP-ribose and cyclic ADP-ribose. In addition to the indirect redox-sensing mechanism through TRPM2, direct redox-sensing mechanisms involving cysteine (Cys) modification has emerged as a mechanism underlying activation of various TRP channels, such as TRPC5, TRPV1, TRPV3, TRPV4, and TRPA1 channels.
In addition to oxidative stress sensing channels, we have identified the TRPA1 channel as a moderate hypoxia sensor. TRPA1 monitors oxygen availability in vagal nerves and glial cells and regulates ventilatory responses to moderate hypoxia.
Given that TRP channels can convert the information of stress into Ca2+ signaling, which regulates numerous cellular processes, such as cell motility, gene transcription, muscle contraction, exocytosis, and survival, it is highly likely that these channels mediate various physiological and pathological processes.
Nobuaki Takahashi Research Group widely investigates roles of redox and hypoxia sensitive TRP channels in the body using knockout mice and some disease model mice. In addition, we investigate when life acquires stress sensing programs through molecular evolutionary studies.
[Publications]
1. Chen S, Takahashi N (Co-First) et al Front Physiol 2020
2. Uchiyama M et al Current Biology 2020
3. Miyake T et al Nature Commun 2016
4. Ogawa N et al J Biol Chem 2016
5. Takahashi N et al Nature Commun 2014
6. Takahashi N et al Front Physiol 2012
7. Takahashi N et al Nature Chem Biol 2011
8. Takahashi N et al Front Pharmacol 2011
9. Takahashi N et al Cell Calcium 2011
10. Bogeski I et al Science Signal 2010
11. Yamamoto S et al Nature Med 2008
12. Takahashi N et al Channels 2008
13. Yoshida T et al Nature Chem Biol 2006
III. Understanding Life by the Power of Chemistry (Chemical Biology)
All the life phenomena are exclusively based on chemical reactions. We try to fully take advantage of our background knowledge of Chemistry in order to view biology and medicine from a different perspective.
Based on physicochemical measurements, we previously determined redox sensitivity of TRP channels and found that TRPA1 has the highest oxidation sensitivity among all TRP channel family members. Currently, we try to address a very fundamental question concerning how oxidative stress is induced in the body in the light of chemical reactions.
[Publication]
Takahashi N et al Nature Chem Biol 2011
