Elucidating the role of metabolic adaptation and cellular stress response in cancer progression and recurrence

Abstract

Cancer metabolism plays a dual role in facilitating ATP synthesis for cancer cell proliferation and in driving malignant transformation and aggressive phenotypes. Prolyl hydroxylase domain-containing protein (PHD) 3 is essential for maintaining cellular metabolic adaptation in cancer by sensing metabolic status and hydroxylating target substrates. However, knowledge regarding the substrate of PHD3 involved in fuel switching in cancer remains limited. Here, we reveal that PHD3 triggers the repression of anaplerosis into the tricarboxylic acid (TCA) cycle through the hydroxylation of pyruvate carboxylase (PC). PHD3 is dual-localized in both the cytosol and mitochondria, where it interacts with PC. Overexpressing PHD3 limits PC activity, consequently impeding cell growth and metastasis while promoting apoptosis. We find that PHD3 expression is strongly increased in subsets of cancer, including clear cell renal cell carcinoma (ccRCC), and is linked to ccRCC progression. Thus, our data identify an unexpected link between PHD3 and PC, and the role of PHD3 in the metabolic dependencies of ccRCC. Cancer recurrence remains an unresolved challenge in cancer treatment, posing a major barrier to achieving complete remission. AML exhibits the highest mortality rate among all blood cancers; however, most patients experience relapse even after achieving complete remission, and the treatment options for relapsed AML are limited. Furthermore, the underlying mechanisms of recurrence are not well understood. Our research explores the connection between AML recurrence and cellular alterations caused by DNA damage. We found that repopulation patterns of damaged AML cells vary with the extent and duration of the damage, suggesting the critical role of extensive damage in both the dormancy and subsequent repopulation of these cells. Interestingly, damaged AML cells exhibit characteristics distinct from those of treatment-naive AML cells, and an increased supply of nutrients significantly increases cell death among dormant AML cells. Additionally, DNA damage alters cellular metabolism in AML cells, including increased fatty acid metabolism and decreased amino acid biosynthesis. In summary, our results demonstrate the significant role that metabolites play in the recurrence of AML under damaging conditions. Therefore, understanding metabolic adaptation and the cellular stress response will contribute to the development of effective treatments for cancer progression and recurrence.