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NVP-BKM120 inhibits colon cancer growth via FoxO3a-dependent PUMA induction

Shida Yang1, Xin Li2, Wenchang Guan3

  • 1Department of Laboratory Medicine, The People's Hospital of Liaoning Province, Shenyang, China.

Oncotarget
|November 16, 2017
PubMed

Insights

NVP-BKM120, a PI3K inhibitor, suppresses colon cancer growth by inducing PUMA, a protein crucial for apoptosis. PUMA induction enhances NVP-BKM120

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • NVP-BKM120 is a PI3K inhibitor in clinical trials for cancer.
  • Its precise mechanisms in colon cancer remain largely unknown.
  • Understanding its action is key for optimizing therapeutic strategies.

Purpose of the Study:

  • To elucidate the mechanisms by which NVP-BKM120 inhibits colon cancer cell growth.
  • To investigate the role of PUMA in NVP-BKM120's anti-cancer effects.
  • To explore NVP-BKM120's synergistic potential with other chemotherapeutics.

Main Methods:

  • Investigated NVP-BKM120 effects on colon cancer cell lines.
  • Analyzed PUMA induction via the FoxO3a pathway after AKT inhibition.
  • Evaluated PUMA's necessity for apoptosis using knockdown/knockout models.
  • Assessed drug synergy with 5-Fluorouracil and regorafenib.
  • Utilized xenograft models to study antitumor effects in vivo.

Main Results:

  • NVP-BKM120 treatment increased PUMA levels, independent of p53 status, via FoxO3a and AKT inhibition.
  • PUMA was essential for NVP-BKM120-induced apoptosis in colon cancer cells.
  • NVP-BKM120 synergized with 5-Fluorouracil and regorafenib to enhance apoptosis through PUMA induction.
  • PUMA deficiency impaired NVP-BKM120's apoptotic and antitumor effects in vivo.

Conclusions:

  • PUMA plays a critical role in mediating the anti-cancer effects of NVP-BKM120.
  • PUMA can serve as a predictive biomarker for NVP-BKM120 sensitivity.
  • These findings have significant implications for the clinical application of NVP-BKM120 in colon cancer treatment.
Keywords:
FoxO3aNVP-BKM120PUMAapoptosiscolon cancer

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