Therapeutic targeting of aldolase a interactions inhibits lung cancer metastasis and prolongs survival

Yu Chan Chang, Jean Chiou, Yi Fang Yang, Chia Yi Su, Yuan Feng Lin, Chia Ning Yang, Pei Jung Lu, Ming Shyan Huang, Chih Jen Yang, Michael Hsiao

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Cancer metabolic reprogramming promotes tumorigenesis and metastasis; however, the underlying molecular mechanisms are still being uncovered. In this study, we show that the glycolytic enzyme aldolase A (ALDOA) is a key enzyme involved in lung cancer metabolic reprogramming and metastasis. Overexpression of ALDOA increased migration and invasion of lung cancer cell lines in vitro and formation of metastatic lung cancer foci in vivo. ALDOA promoted metastasis independent of its enzymatic activity. Immunoprecipitation and proteomic analyses revealed γ-actin binds to ALDOA; blocking this interaction using specific peptides decreased metastasis both in vitro and in vivo. Screening of clinically available drugs based on the crystal structure of ALDOA identified raltegravir, an antiretroviral agent that targets HIV integrase, as a pharmacologic inhibitor of ALDOA-γ-actin binding that produced antimetastatic and survival benefits in a xenograft model with no significant toxicity. In summary, ALDOA promotes lung cancer metastasis by interacting with γ-actin. Targeting this interaction provides a new therapeutic strategy to treat lung cancer metastasis. Significance: This study demonstrates the role of aldolase A and its interaction with γ-actin in the metastasis of non- small lung cancer and that blocking this interaction could be an effective cancer treatment.

Original languageEnglish
Pages (from-to)4754-4766
Number of pages13
JournalCancer Research
Volume79
Issue number18
DOIs
Publication statusPublished - 2019 Sep 15

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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    Chang, Y. C., Chiou, J., Yang, Y. F., Su, C. Y., Lin, Y. F., Yang, C. N., Lu, P. J., Huang, M. S., Yang, C. J., & Hsiao, M. (2019). Therapeutic targeting of aldolase a interactions inhibits lung cancer metastasis and prolongs survival. Cancer Research, 79(18), 4754-4766. https://doi.org/10.1158/0008-5472.CAN-18-4080