SHMT2-mediated mitochondrial serine metabolism drives 5-FU resistance by fueling nucleotide biosynthesis

• DOI: 10.1016/j.celrep.2022.111233
• Publication Date: 2022-08-16T14:53:54Z
• Authors: Erica Pranzini; Elisa Pardella; Livio Muccillo; Angela Leo; Ilaria Nesi; Alice Santi; Matteo Parri; Tong Zhang; Alejandro Huerta ...; Tiziano Lottini; Lina Sabatino; Anna Caselli; Annarosa Arcangeli; Giovanni Raugei; Vittorio Colantuoni; Paolo Cirri; Paola Chiarugi; Oliver D.K. Maddocks; Paolo Paoli; Maria Letizia Taddei
• Keywords: 0303 health sciences; Nucleotides; Mitochondria; 3. Good health; 03 medical and health sciences; Drug Resistance, Neoplasm; Cell Line, Tumor; Neoplasms; colon cancer, chemoresistance, 5-FU, cancer cell metabolism, serine metabolism; Serine; Humans; Fluorouracil; Colorectal Neoplasms

5-Fluorouracil (5-FU) is a key component of chemotherapy for colorectal cancer (CRC). 5-FU efficacy established by intracellular levels folate cofactors and DNA damage repair strategies. However, drug resistance still represents major challenge. Here, we report that alterations in serine metabolism affect sensitivity vitro vivo CRC models. In particular, 5-FU-resistant cells display strong dependency achieved either upregulating endogenous synthesis or increasing exogenous uptake. Importantly, regardless the feeder strategy, hydroxymethyltransferase-2 (SHMT2)-driven compartmentalization one-carbon inside mitochondria specific adaptation resistant to support purine biosynthesis potentiate response. Interfering with availability affecting its mitochondrial revert resistance. These data disclose relevant mechanism use supporting provide perspectives therapeutic approaches.