Abstract
Metabolic reprogramming is a core hallmark of cancer and is key for tumorigenesis and tumor progression. Investigation of metabolic perturbation by anti-cancer compounds would allow a thorough understanding of the underlying mechanisms of these agents and identification of new anti-cancer targets. Here, we demonstrated that the administration of oleanolic acid (OA) rapidly altered cancer metabolism, particularly suppressing the purine salvage pathway (PSP). PSP restoration significantly opposed OA-induced DNA replication and cell proliferation arrest, underscoring the importance of this pathway for the anti-cancer activity of OA. Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and 5′-nucleotidase (5′-NT), two metabolic enzymes essential for PSP activity, were promptly degraded by OA via the lysosome pathway. Mechanistically, OA selectively targeted superoxide dismutase 1 (SOD1) and yielded reactive oxygen species (ROS) to activate the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin complex 1 (mTORC1)/macroautophagy pathway, thus eliciting lysosomal degradation of HGPRT and 5′-NT. Furthermore, we found that the PSP was overactivated in human lung and breast cancers, with a negative correlation with patient survival. The results of this study elucidated a new anti-cancer mechanism of OA by restraining the PSP via the SOD1/ROS/AMPK/mTORC1/macroautophagy/lysosomal pathway. We also identified the PSP as a new target for cancer treatment and highlighted OA as a potential therapeutic agent for cancers with high PSP activity.
Highlights
Cancer is a devastating disease and the second-leading cause of deaths worldwide.[1]
Unc-51-like autophagy activating kinase 1 (ULK1) is a key component of the autophagy apparatus that is activated by AMPK via phosphorylation of Ser[555] or repressed by mTORC1 via phosphorylation of Ser757.31 Our results showed that OA treatment significantly reduced phosphorylated ULK1 at Ser[757] but did not influence phosphorylated ULK1 at Ser[555] (Figure 6A)
We determined that the purine salvage pathway (PSP) is a key metabolic target through which OA demonstrates anti-cancer activity
Summary
Cancer is a devastating disease and the second-leading cause of deaths worldwide.[1]. Molecular Therapy: Oncolytics Vol 23 December 2021 a 2021 The Author(s). Molecular Therapy: Oncolytics glycolysis, TCA cycle, and synthesis of nonessential amino acids, respectively.[14,15,16] Nucleotide synthesis is hyperactive in cancer cells to produce abundant genetic material, including DNA and RNA.[17,18] OA reportedly restrained glycolysis and lipid biosynthesis in cancer cells.[9] the effects of OA on the metabolism of cancer cells and its major downstream metabolic targets remain to be elucidated
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