Uncovering the Metabolic Origin of Aspartate for Tumor Growth Using an Integrated Molecular Deactivator
Ruixue Duan, Yuanyuan Xu, Xuemei Zeng, Jiahui Xu, Liangliang Liang, Zhenzhen Zhang, Zhimin Wang, Xiaoxiao Jiang, Bengang Xing, Bifeng Liu, Angelo H. All, Xiaosong Li, Luke P. Lee, Xiaogang Liu
Abstract
Reprogrammed glucose metabolism is vital for cancer cells, but aspartate, an intermediate metabolic product, is the limiting factor for cancer cell proliferation. However, due to the complexity of metabolic pathways, it remains unclear whether glucose is the primary source of endogenous aspartate. Here, we report the design of an innovative molecular deactivator, based on a multifunctional upconversion nanoprobe, to explore the link between glucose and aspartate. This molecular deactivator mainly works in the acidic, hypoxic tumor microenvironment and deactivates multiple types of glucose transporters on cancer cell membranes upon illumination at 980 nm. Cancer cell proliferation in vivo is strongly inhibited by blocking glucose transporters. Our experimental data confirm that the cellular synthesis of aspartate for tumor growth is glucose-dependent. This work also demonstrates the untapped potential of molecularly engineered upconversion nanoprobes for discovering hidden metabolic pathways and improving therapeutic efficacy of conventional antitumor drugs.