SIRT4 Overcomes 5-Fluorouracil Associated Chemoresistance by Inhibiting Autophagy through Inhibition of ammonia production

Abstract

Abstract 5-Fluorouracil (5-FU) is a first-line chemotherapy agent for colorectal cancer (CRC), but the emergence of chemoresistance has affected its use. Our preliminary results found that SIRT4 levels were reduced in CRC and correlated with poor prognosis. Here, we show that SIRT4 enhances the sensitivity of CRC cells to 5-FU. Mechanistically, SIRT4 inhibits autophagy flow in CRC cells, and, inhibition of autophagy by bafilomycin or shATG5 counteracts the increased sensitivity of CRC cells to 5-FU caused by SIRT4. Further, SIRT4 inhibited glutamine metabolism and thus ammonia production in CRC cells by inhibiting glutamate dehydrogenase (GDH), whereas inhibition of glutamine metabolism by BPTES or addition of ammonium chloride to the medium counteracted the inhibition of autophagy caused by SIRT4. Finally, inhibition of glutamine metabolism or addition of ammonium chloride to the medium counteracted the difference in sensitivity of CRC cells to 5-FU caused by SIRT4. Together, the current findings identify a novel role of SIRT4 in autophagy manipulation and demonstrate the molecular mechanism behind SIRT4 in enhancing the sensitivity of colorectal cancer cells to 5-FU, providing a promising strategy to increase the efficacy of 5-FU for the treatment of colorectal cancer.