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EPS8 regulates proliferation, apoptosis and chemosensitivity in BCR-ABL positive cells via the BCR-ABL/PI3K/AKT/mTOR

Rui Huang1, Huimin Liu1, Yiran Chen1

  • 1Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, P.R. China.

Oncology Reports
|December 2, 2017
PubMed

Insights

Epidermal growth factor receptor kinase substrate 8 (EPS8) is upregulated in chronic myeloid leukemia (CML) and drives cancer cell growth and resistance. Targeting EPS8 may offer a new therapeutic strategy for CML patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Hematology

Background:

  • Tyrosine kinase inhibitors (TKIs) have improved survival in chronic myeloid leukemia (CML), but drug resistance remains a significant challenge.
  • Epidermal growth factor receptor kinase substrate 8 (EPS8) is an oncogene implicated in solid tumors and acute leukemia chemoresistance, but its role in CML is unknown.
  • Identifying novel therapeutic targets is crucial for overcoming TKI resistance in CML.

Purpose of the Study:

  • To investigate the role of EPS8 in chronic myeloid leukemia (CML).
  • To determine the effect of EPS8 on CML cell biological functions and chemosensitivity.
  • To elucidate the underlying molecular mechanisms of EPS8 in CML.

Main Methods:

  • Quantitative reverse transcription polymerase chain reaction (q-RT-PCR) to measure EPS8 mRNA levels.
  • EPS8 knockdown in K562 CML cell line and 32D-p210BCR/ABL-T315I cells.
  • Assessment of cell proliferation, apoptosis, adhesion, migration, and chemosensitivity.
  • Western blotting to analyze signaling pathways (p-BCR/ABL, AKT/mTOR).
  • In vivo studies using BALB/c nude mice.

Main Results:

  • CML patients exhibited significantly higher EPS8 mRNA levels in bone marrow mononuclear cells compared to healthy controls.
  • EPS8 knockdown in K562 cells led to reduced proliferation, increased apoptosis, and impaired adhesion/migration.
  • Attenuating EPS8 enhanced chemosensitivity in both imatinib-sensitive and imatinib-resistant CML cells.
  • EPS8 knockdown downregulated p-BCR/ABL and the downstream AKT/mTOR signaling pathway.
  • In vivo, EPS8 knockdown suppressed K562 cell proliferation in mice.

Conclusions:

  • EPS8 plays a critical role in regulating proliferation, apoptosis, and chemosensitivity in BCR-ABL positive CML cells.
  • The BCR-ABL/PI3K/AKT/mTOR pathway is involved in EPS8-mediated regulation of CML cell functions.
  • Targeting EPS8, either alone or in combination with TKIs, represents a potential therapeutic strategy for CML.

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