Inhibition of hypoxia-induced macropinocytosis in future cancer therapeutic strategies

In general, the prognosis for liver cancer is poor because patients are often diagnosed with liver cancer in advanced stage, while its cancer cells can still survive in hypoxia.1,2 In a recent study conducted by Wong CL and colleagues from the Department of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, published in Nature Communications, it was found that hypoxia-induced macropinocytosis is a new metabolic mechanism in liver cancer cells, by which causing the engulfment of extracellular fluid and the subsequent protein digestion to support the unlimited growth of hepatocellular carcinoma (HCC).1 The breakthrough discovery indicates that inhibiting hypoxia-induced macropinocytosis could be a novel and effective therapeutic approach for HCC.1 This study could also be applied to other solid cancer types with hypoxia.1

Liver cancer is the most frequent cause of cancer death worldwide and was the fifth most common cancer in Hong Kong, accounting for 5.3% of all new cancer cases in 2019.2,3 HCC arises from hepatocytes, accounting for 90% of primary liver cancer cases.1 The risk factors of liver cancer include hepatitis B virus, hepatitis C virus, fatty liver disease and alcohol-related cirrhosis, to name a few.2 Despite the increasing availability of therapeutic options for advanced stage of HCC, these patients only have a median life expectancy of less than 2 years.1 Therefore, it is of great importance to identify new molecular cascades that support HCC cell survival so as to attain more effective therapeutic targets.1

HCC cells are resilient to declining in oxygen environment (i.e., hypoxia), which is commonly found in all solid cancer types due to abnormal vasculature.1 Cells adapt to hypoxia through heterodimeric proteins consisting of hypoxia-inducible factor (HIF)-1/-2α and HIF-1β subunits.1 When nutrients, such as glucose, glutamine (Gln) and amino acids (AAs), become limited, cancer cells will rely on macropinocytosis to scavenge extracellular nutrients for use as fuels to sustain its growth.1 Besides, cancer cells may use macropinocytosis to take up necrotic cell debris and reuse proteins, lipids and nucleotides from dying cells as a nutrient source in case of inadequate nutrient supply.1

In this study, investigators found that hypoxia stabilized HIF-1 transcriptionally activated EH-domain containing 2 (EHD2), and subsequently, EHD2 interacted with actin filaments to promote membrane ruffling formation, which was the first and critical step in macropinocytosis initiation in hypoxic HCC cells.1 Furthermore, hypoxia-induced macropinocytosis promoted the engulfment of extracellular proteins such as albumin, and after protein digestion, the degraded proteins were integrated into the intracellular amino acid, serving as a fuel to support HCC cell proliferation under hypoxic conditions.1 Their findings also justified that HIF-1/EHD2-mediated macropinocytosis could be initiated in the absence of amino acids.1

Of note, this study showed that the germline or somatic deletion of EHD2 in mice prevented the growth of HCC induced by hepatocarcinogen or liver-specific Tp53 knockout (KO) or Kelch-like ECH-associated protein 1 (Keap1) KO with c-Myc overexpression (OE).1 The treatment of digoxin (HIF inhibitor) or IPA-3 (macropinocytosis inhibitor) achieved a more than 50% inhibition of the tumor burden in mouse HCC models.1 Apart from the observation that digoxin repressed macropinocytosis and the growth of HCC, IPA-3 that targeted PAK1 also effectively perturbed the HCC growth by blocking macropinosome formation, a more specific macropinocytosis inhibitor that has yet to be developed, particularly for various steps in macropinocytosis.1

Overall, HIF-1 is a regulatory pathway in HCC cells to activate the transcription of a membrane ruffling protein, i.e., EHD2, to initiate macropinocytosis.1 Therefore, KO of HIF-1 or EHD2 represses hypoxia-induced macropinocytosis and prevents hypoxic HCC cells from scavenging proteins for its growth.1 Since hypoxia also occurs in other solid cancer types, the future innovative cancer therapeutic strategies against macropinocytosis could be useful for all types of solid cancer.1

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