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Halofuginone dually regulates autophagic flux through nutrient-sensing pathways in colorectal cancer

Guo-Qing Chen1,2, Rui-Hong Gong1, Da-Jian Yang2

  • 1Laboratory of Brain and Gut Research, Center for Clinical Research on Chinese Medicine, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.

Cell Death & Disease
|May 12, 2017
PubMed

Insights

Halofuginone (HF) shows dual regulation of autophagy in colorectal cancer (CRC) by modulating ULK1 activity based on nutrient availability, impacting tumor growth.

Area of Science:

  • Cellular Biology
  • Cancer Research
  • Metabolism

Background:

  • Autophagy plays a crucial role in cellular metabolism and tumorigenesis.
  • Halofuginone (HF) previously demonstrated anticancer effects in colorectal cancer (CRC) by inhibiting the Akt/mTORC1 pathway.
  • The precise mechanisms by which HF influences autophagy and metabolism in cancer remain unclear.

Purpose of the Study:

  • To elucidate how halofuginone (HF) regulates autophagy and metabolism in colorectal cancer (CRC) under varying nutritional conditions.
  • To investigate the role of ULK1, Akt/mTORC1, and LKB1/AMPK signaling pathways in HF-mediated autophagy modulation.
  • To determine the impact of HF on glucose metabolism and tumor growth in vivo.

Main Methods:

  • Investigated HF effects on ULK1 phosphorylation at specific sites (Ser757, Ser317, Ser777) in relation to Akt/mTORC1 and LKB1/AMPK signaling.
  • Assessed Atg7-dependent autophagosome formation under nutrient-rich and nutrient-poor conditions.
  • Analyzed HF's impact on glycolysis and gluconeogenesis.
  • Evaluated HF's anti-tumor efficacy in xenograft mouse models with different dietary conditions.

Main Results:

  • HF activates ULK1 via Akt/mTORC1, inducing autophagy under nutrient-rich conditions.
  • HF inactivates ULK1 via LKB1/AMPK, inhibiting autophagy under nutrient-poor conditions.
  • HF modulates glucose metabolism (inhibiting glycolysis or gluconeogenesis) in an Atg7-dependent manner.
  • HF treatment suppressed tumor growth in vivo, irrespective of diet, due to dual autophagy regulation.

Conclusions:

  • Halofuginone exhibits a context-dependent dual role in autophagy modulation in colorectal cancer.
  • HF's regulation of autophagy is intricately linked to nutritional status and impacts glucose metabolism.
  • These findings highlight HF as a potential therapeutic agent for CRC, leveraging its ability to dual-regulate autophagy for anti-tumor effects.

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