bims-momema Biomed News
on Molecular mechanisms of macropinocytosis
Issue of 2022–03–20
two papers selected by
Harilaos Filippakis, Harvard University
  1. Macropinocytosis is an alternative pathway of cysteine acquisition and mitigates sorafenib-induced ferroptosis in hepatocellular carcinoma.
  2. Lysosomal inhibition sensitizes TMEM16A-expressing cancer cells to chemotherapy.
  1. J Exp Clin Cancer Res. 2022 Mar 14. 41(1): 98
    Macropinocytosis is an alternative pathway of cysteine acquisition and mitigates sorafenib-induced ferroptosis in hepatocellular carcinoma.
    Jun-Kyu Byun, Seunghyeong Lee, Gil Won Kang, Yu Rim Lee, Soo Young Park, Im-Sook Song, Jae Won Yun, Jaebon Lee, Yeon-Kyung Choi, Keun-Gyu Park.
       BACKGROUND: Macropinocytosis, an important nutrient-scavenging pathway in certain cancer cells, allows cells to compensate for intracellular amino acid deficiency under nutrient-poor conditions. Ferroptosis caused by cysteine depletion plays a pivotal role in sorafenib responses during hepatocellular carcinoma (HCC) therapy. However, it is not known whether macropinocytosis functions as an alternative pathway to acquire cysteine in sorafenib-treated HCC, and whether it subsequently mitigates sorafenib-induced ferroptosis. This study aimed to investigate whether sorafenib drives macropinocytosis induction, and how macropinocytosis confers ferroptosis resistance on HCC cells.
    METHODS: Macropinocytosis, both in HCC cells and HCC tissues, was evaluated by measuring TMR-dextran uptake or lysosomal degradation of DQ-BSA, and ferroptosis was evaluated via C11-BODIPY fluorescence and 4-HNE staining. Sorafenib-induced ferroptosis and macropinocytosis were validated in tumor tissues taken from HCC patients who underwent ultrasound-guided needle biopsy.
    RESULTS: Sorafenib increased macropinocytosis in human HCC specimens and xenografted HCC tissues. Sorafenib-induced mitochondrial dysfunction was responsible for activation of PI3K-RAC1-PAK1 signaling, and amplified macropinocytosis in HCC. Importantly, macropinocytosis prevented sorafenib-induced ferroptosis by replenishing intracellular cysteine that was depleted by sorafenib treatment; this rendered HCC cells resistant to sorafenib. Finally, inhibition of macropinocytosis by amiloride markedly enhanced the anti-tumor effect of sorafenib, and sensitized resistant tumors to sorafenib.
    CONCLUSION: In summary, sorafenib induced macropinocytosis, which conferred drug resistance by mitigating sorafenib-induced ferroptosis. Thus, targeting macropinocytosis is a promising therapeutic strategy to facilitate ferroptosis-based therapy for HCC.
    Keywords:  Ferroptosis; Hepatocellular carcinoma; Macropinocytosis; Sorafenib; Sorafenib resistance
    DOI:  https://doi.org/10.1186/s13046-022-02296-3
  2. Proc Natl Acad Sci U S A. 2022 Mar 22. 119(12): e2100670119
    Lysosomal inhibition sensitizes TMEM16A-expressing cancer cells to chemotherapy.
    Avani Vyas, Roberto Gomez-Casal, Silvia Cruz-Rangel, Hugo Villanueva, Andrew G Sikora, Pavithra Rajagopalan, Devraj Basu, Jonathan Pacheco, Gerald R V Hammond, Kirill Kiselyov, Umamaheswar Duvvuri.
      SignificanceCisplatin is the first line therapy for patients with head and neck cancer. However, resistance to cisplatin remains a major concern. High expression of the calcium-activated chloride channel TMEM16A in tumors portends poor survival in these patients, possibly because of drug resistance. Here, we show that TMEM16A drives the sequestration of cisplatin into lysosomes. Subsequently, cisplatin is expelled via the delivery of lysosomes to the cell surface. We show that TMEM16A enhances this process, thereby promoting cisplatin resistance. We also show that lysosomal inhibition synergizes with cisplatin to induce tumor cell death. Our data uncovers a new fundamental feature of both lysosomal physiology and cancer cell biology that can potentially impact the treatment of patients with head and neck cancer.
    Keywords:  MITF; TMEM16A; cisplatin; hydroxychloroquine; lysosomal flux
    DOI:  https://doi.org/10.1073/pnas.2100670119
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