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mTOR up-regulation of PFKFB3 is essential for acute myeloid leukemia cell survival

Yonghuai Feng1, Liusong Wu2

  • 1Department of Hematology, Peking University People's Hospital, Beijing, China; Institute of Hematology, Peking University, Beijing, China; Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China; Collaborative Innovation Center of Hematology, Peking University, Beijing, China.

Biochemical and Biophysical Research Communications
|January 14, 2017
PubMed

Insights

Mammalian target of rapamycin (mTOR) hyper-activation in acute myeloid leukemia (AML) drives cancer cell survival by up-regulating PFKFB3. Inhibiting PFKFB3 offers a promising therapeutic strategy for AML patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Mammalian target of rapamycin (mTOR) pathway activation is common in acute myeloid leukemia (AML).
  • The specific roles and downstream targets of mTOR in AML remain largely uncharacterized.
  • Understanding mTOR signaling is crucial for developing targeted AML therapies.

Purpose of the Study:

  • To identify novel downstream targets of mTOR signaling in AML.
  • To investigate the functional significance of PFKFB3 in AML cell proliferation and survival.
  • To explore PFKFB3 as a potential therapeutic target in AML.

Main Methods:

  • Utilized cell lines (THP1, OCI-AML3) with TSC2 knockdown to study mTOR signaling.
  • Investigated the effect of PFKFB3 silencing on glycolysis and cell proliferation.
  • Examined the impact of rapamycin, Raptor, and Rictor modulation on PFKFB3 expression.
  • Assessed the role of hypoxia-inducible factor 1α (HIF1α) in mTOR-mediated PFKFB3 regulation.

Main Results:

  • PFKFB3 was identified as a novel downstream substrate of mTOR signaling, with its expression augmented upon TSC2 knockdown.
  • Silencing PFKFB3 suppressed glycolysis and proliferation in AML cells and induced apoptosis.
  • mTORC1-mediated upregulation of PFKFB3 was dependent on HIF1α.
  • Combined inhibition of PFKFB3 and mTOR synergistically reduced AML cell proliferation.

Conclusions:

  • mTOR-driven upregulation of PFKFB3 is essential for AML cell survival.
  • PFKFB3 represents a promising therapeutic target for AML patients with mTOR hyper-activation.
  • Targeting the mTOR-PFKFB3 axis offers a potential strategy for AML treatment.
Keywords:
Acute myeloid leukemiaPFKFB3mTOR

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