Conflict of Interest: The authors declare no conflict of interest

Study Sponsor Note: The study sponsors are listed in the acknowledgement section and they had no role in the study design in the collection, analysis, and interpretation of data.

ACKNOWLEDGMENTS:

A part of Tuo Hu’s stipend was supported by the China Scholarship Council (CSC) program.

Author Contributions: T.H., S.K.S., E.V., and P.K.S. designed the research; T.H., S.K.S., E.V., C.H., D.W., R.J.K., K.J., K.S., N.V.C., R.T., C.G.P., and X.F. performed research; K.S.A, D.M., R.H., F.Y., A.L., C.S., P.L., K.M., D.R., S.C., S.V., M.T., A.M., J.A., E.V., D.T., and P.K.S. contributed reagents/analytic tools; T.H., S.K.S., E.V., C.H., D.W., K.S., and P.K.S. analyzed data; T.H., S.K.S., E.V., C.H., D.W., N.J.M., S.M., S.C., M.T., A.M., E.V., and P.K.S. contributed to project discussions; T.H., and P.K.S. wrote the manuscript.

Conflicts of interest: The authors disclose no conflicts.

Funding:

This work was supported in part by the funding from National Institutes of Health (R01 CA216853, R01CA210439, R01CA163649, and P01 CA2117798, NCI) to PKS, (SPORE, 2P50 CA127297, NCI) to PKS, the Italian AIRC 2016 (n. 19162) to AM, and (P30 CA036727, NCI) for supporting shared resources.

WHAT YOU NEED TO KNOW

BACKGROUND AND CONTEXT

• PDAC cells with activating KRAS mutations utilize glutamine in a non-canonical way via the GOT2-GOT1-ME1 pathway. SIRT5 has pleiotropic roles, serving as an oncogene and tumor suppressor in different cancers.

NEW FINDINGS

• SIRT5 is a novel tumor suppressor for pancreatic cancer and genetically targeting SIRT5 makes PDAC tumors more aggressive.

• SIRT5 negatively regulates non-canonical glutamine metabolism via direct post-translational modifications of GOT1.

• Activation of SIRT5 with a novel small molecule is a potential new therapy for PDAC with low SIRT5 levels.

LIMITATIONS

• This study was conducted in PDAC cell lines, genetically-engineered mice models, human tissue samples (tissue microarrays, PDAC organoids, and patient-derived xenografts). More work needs to be done in human patients.

IMPACT

• SIRT5 activation (small-molecule SIRT5-activator MC3138) combined with gemcitabine may lead to a novel safe and effective therapy for PDAC patients with low tumoral SIRT5 expression.