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

Abstract

Autophagy has a key role in metabolism and impacts on tumorigenesis. Our previous study found that halofuginone (HF) exerts anticancer activity in colorectal cancer (CRC) by downregulating Akt/mTORC1 (mechanistic target of rapamycin complex 1) signaling pathway. But whether and how HF regulates autophagy and metabolism to inhibit cancer growth remains an open question. Here, we unveil that HF activates ULK1 by downregulation of its phosphorylation site at Ser757 through Akt/mTORC1 signaling pathway, resulting in induction of autophagic flux under nutrient-rich condition. On the other hand, HF inactivates ULK1 by downregulation of its phosphorylation sites at Ser317 and Ser777 through LKB1/AMPK signaling pathway, resulting in autophagic inhibition under nutrient-poor condition. Furthermore, Atg7-dependent autophagosome formation is also induced under nutrient-rich condition or blocked in nutrient-poor environment, respectively, upon HF treatment. More interestingly, we also found that HF inhibits glycolysis under nutrient-rich condition, whereas inhibits gluconeogenesis under nutrient-poor condition in an Atg7-dependent manner, suggesting that autophagy has a pivotal role of glucose metabolism upon HF treatment. Subsequent studies showed that HF treatment retarded tumor growth in xenograft mice fed with either standard chow diet or caloric restriction through dual regulation of autophagy in vivo. Together, HF has a dual role in autophagic modulation depending on nutritional conditions for anti-CRC.

Amino acid response by Halofuginone in Cancer cells triggers autophagy through proteasome degradation of mTOR

“…Error bars: standard deviation. Statistically significant differences between fluorescence intensity densities after to before HF, or after to before PRO in the presence of HF are shown (*, p ≤ 0.05) by inactivating mTORC1 and the resulting dephosphorylation of ULK1 at Ser 757 [42]. Here, we show that mTORC1 specifically located at the lysosome level links the AAR induced by HF with the autophagy pathway.…”

“…HF elicits also a general anti-inflammatory response by inhibiting the differentiation of inflammatory Th17 cells, and this effect was clearly sue to the induction of the AAR [13][14][15]. HF is currently employed in clinical trials due to its therapeutic potential in fibrotic diseases and cancer [42,[54][55][56][57][58][59] (https://clinicaltrials.gov/). The data here reported strongly support the view that the therapeutic potential of HF is linked to its ability to induce autophagy, and eventually cell death, besides its modulatory effect on protein synthesis.…”

Amino Assets: How Amino Acids Support Immunity

“…d Halofuginone mimics amino acid starvation by pharmacologically activating GCN2. This compound reduces gut inflammation(Ravindran et al, 2016) and induces autophagy(Chen et al, 2017), which may increase longevity by opposing the age-related decline in immune cell function. d Modulating amino acid supply to tumors in combination with checkpoint blockade is a promising anti-cancer strategy, as observed for cysteine/cystine depletion in a melanoma model(Wang et al, 2019a).…”

Strategies to target energy metabolism in consensus molecular subtype 3 along with Kirsten rat sarcoma viral oncogene homolog mutations for colorectal cancer therapy

“…Several agents have been identified to free VDAC1–HK compounds, including HK‐I‐ and HK‐II‐derived peptides (G. Q. Chen et al, ). Recently, the synthetic VDAC1 peptide has been shown to interact directly with HK‐I and HK‐II, leading to their separation from VDAC1 (G. Q. Chen et al, ). VDAC1‐based peptide and the binding site of VDAC1, thereby, reduce glycolysis, and reduce Δ Ψ and cellular ATP levels (L. Wang et al, ), impact energy balance inside body, reduce the apoptosis induced by cancer cells self‐defense mechanism and small molecules (Roberts & Miyamoto, ).…”