title: Differential Sensitivities of Fast- and Slow-Cycling Cancer Cells to Inosine Monophosphate Dehydrogenase 2 Inhibition by Mycophenolic Acid.
abstract: As uncontrolled cell proliferation requires nucleotide biosynthesis, inhibiting enzymes that mediate nucleotide biosynthesis constitutes a rational approach to the management of oncological diseases. In practice, however, results of this strategy are mixed and thus elucidation of the mechanisms by which cancer cells evade the effect of nucleotide biosynthesis restriction is urgently needed. Here we explored the notion that intrinsic differences in cancer cell cycle velocity are important in the resistance toward inhibition of inosine monophosphate dehydrogenase (IMPDH) by mycophenolic acid (MPA). In short-term experiments, MPA treatment of fast-growing cancer cells effectively elicited G0/G1 arrest and provoked apoptosis, thus inhibiting cell proliferation and colony formation. Forced expression of a mutated IMPDH2, lacking a binding site for MPA but retaining enzymatic activity, resulted in complete resistance of cancer cells to MPA. In nude mice subcutaneously engrafted with HeLa cells, MPA moderately delayed tumor formation by inhibiting cell proliferation and inducing apoptosis. Importantly, we developed a lentiviral vector-based Tet-on label-retaining system that enables to identify, isolate and functionally characterize slow-cycling or so-called label-retaining cells (LRCs)in vitroandin vivo. We surprisingly found the presence of LRCs in fast-growing tumors. LRCs were superior in colony formation, tumor initiation and resistance to MPA as compared with fast-cycling cells. Thus, the slow-cycling compartment of cancer seems predominantly responsible for resistance to MPA.
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.|Bio-X Center, College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou, China.
authors.forename: Kan
authors.initials: K
authors.lastname: Chen
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Wanlu
authors.initials: W
authors.lastname: Cao
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Juan
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Dave
authors.initials: D
authors.lastname: Sprengers
authors.affiliation: Laboratory of Medical Genetics, Biomolecular Research Center, Wijaya Kusuma University, Surabaya, Indonesia.
authors.forename: Pratika Y
authors.initials: PY
authors.lastname: Hernanda
authors.affiliation: Bio-X Center, College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou, China.
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Kong
authors.affiliation: Department of Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Luc J W
authors.initials: LJW
authors.lastname: van der Laan
authors.affiliation: Department of Surgery, Hong Kong University, Hong Kong, China.
authors.forename: Kwan
authors.initials: K
authors.lastname: Man
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Jaap
authors.initials: J
authors.lastname: Kwekkeboom
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Herold J
authors.initials: HJ
authors.lastname: Metselaar
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Maikel P
authors.initials: MP
authors.lastname: Peppelenbosch
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Qiuwei
authors.initials: Q
authors.lastname: Pan