2. Academic Validation
  3. Metabolic enzyme LDHA activates Rac1 GTPase as a noncanonical mechanism to promote cancer

Metabolic enzyme LDHA activates Rac1 GTPase as a noncanonical mechanism to promote cancer

  • Nat Metab. 2022 Dec;4(12):1830-1846. doi: 10.1038/s42255-022-00708-4.
Juan Liu 1,  Cen Zhang 1,  Tianliang Zhang 1,  Chun-Yuan Chang 1,  Jianming Wang 1,  Ludvinna Bazile 1,  Lanjing Zhang 2 3,  Bruce G Haffty 1,  Wenwei Hu 4 5,  Zhaohui Feng 6 7
Affiliations

Affiliations

  • 1 Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers-The State University of New Jersey, New Brunswick, NJ, USA.
  • 2 Department of Biological Sciences, Rutgers-The State University of New Jersey, Newark, NJ, USA.
  • 3 Department of Pathology, Princeton Medical Center, Plainsboro, NJ, USA.
  • 4 Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers-The State University of New Jersey, New Brunswick, NJ, USA. wh221@cinj.rutgers.edu.
  • 5 Department of Pharmacology, Rutgers-The State University of New Jersey, Piscataway, NJ, USA. wh221@cinj.rutgers.edu.
  • 6 Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers-The State University of New Jersey, New Brunswick, NJ, USA. fengzh@cinj.rutgers.edu.
  • 7 Department of Pharmacology, Rutgers-The State University of New Jersey, Piscataway, NJ, USA. fengzh@cinj.rutgers.edu.
PMID: 36536137 DOI: 10.1038/s42255-022-00708-4
Abstract

The glycolytic enzyme Lactate Dehydrogenase A (LDHA) is frequently overexpressed in Cancer, which promotes glycolysis and Cancer. The oncogenic effect of LDHA has been attributed to its glycolytic Enzyme activity. Here we report an unexpected noncanonical oncogenic mechanism of LDHA; LDHA activates small GTPase Rac1 to promote Cancer independently of its glycolytic Enzyme activity. Mechanistically, LDHA interacts with the active form of Rac1, Rac1-GTP, to inhibit Rac1-GTP interaction with its negative regulator, GTPase-activating proteins, leading to Rac1 activation in Cancer cells and mouse tissues. In clinical breast Cancer specimens, LDHA overexpression is associated with higher Rac1 activity. Rac1 inhibition suppresses the oncogenic effect of LDHA. Combination inhibition of LDHA Enzyme activity and Rac1 activity by small-molecule inhibitors displays a synergistic inhibitory effect on breast cancers with LDHA overexpression. These results reveal a critical oncogenic mechanism of LDHA and suggest a promising therapeutic strategy for breast cancers with LDHA overexpression.

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