Spheroid cancer stem cells display reprogrammed metabolism and obtain energy by actively running the tricarboxylic acid (TCA) cycle

// Masakazu Sato 1 , Kei Kawana 1 , Katsuyuki Adachi 1 , Asaha Fujimoto 1 , Mitsuyo Yoshida 1 , Hiroe Nakamura 1 , Haruka Nishida 1 , Tomoko Inoue 1 , Ayumi Taguchi 1 , Juri Takahashi 1 , Satoko Eguchi 1 , Aki Yamashita 1 , Kensuke Tomio 1 , Osamu Wada-Hiraike 1 , Katsutoshi Oda 1 , Takeshi Nagamatsu 1 , Yutaka Osuga 1 , Tomoyuki Fujii 1 1 Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan Correspondence to: Kei Kawana, email: kkawana-tky@umin.org Keywords: cancer stem cell (CSC), metabolomics, ovarian cancer, cervical cancer, tricarboxylic acid (TCA) cycle Received: February 01, 2016      Accepted: March 28, 2016      Published: April 23, 2016 ABSTRACT The Warburg effect is a metabolic hallmark of cancer cells; cancer cells, unlike normal cells, exclusively activate glycolysis, even in the presence of enough oxygen. On the other hand, intratumoral heterogeneity is currently of interest in cancer research, including that involving cancer stem cells (CSCs). In the present study, we attempted to gain an understanding of metabolism in CSCs that is distinct from that in non-CSCs. After forming spheroids from the OVTOKO (ovarian clear cell adenocarcinoma) and SiHa (cervical squamous cell carcinoma) cell lines, the metabolites of these cells were compared with the metabolites of cancer cells that were cultured in adherent plates. A principle components analysis clearly divided their metabolic features. Amino acids that participate in tricarboxylic acid (TCA) cycle reactions, such as serine and glutamine, were significantly increased in the spheroids. Indeed, spheroids from each cell line contained more total adenylates than did their corresponding cells in adherent cultures. This study demonstrated that cancer metabolism is not limited to aerobic glycolysis (i.e. the Warburg effect), but is flexible and context-dependent. In addition, activation of TCA cycles was suggested to be a metabolic feature of CSCs that was distinct from non-CSCs. The amino acid metabolic pathways discussed here are already considered as targets for cancer therapy, and they are additionally proposed as potential targets for CSC treatment.