Endocytosis and Cancer

Mellman, Ira; Yarden, Yosef

doi:10.1101/cshperspect.a016949

Cited by 340 publications

(316 citation statements)

References 174 publications

(146 reference statements)

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“…These alterations include global changes in trafficking networks, and altered trafficking of receptor tyrosine kinases and integrins (Mellman and Yarden, 2013). Intuitively, it might be imagined that such trafficking changes will also include an increased turnover and destruction of ECM components by endocytosis, which will, in turn, favor invasion and metastasis.…”

Section: Discussionmentioning

confidence: 99%

Endocytic trafficking of laminin is controlled by dystroglycan and disrupted in cancers

Leonoudakis

Huang

Akhavan

et al. 2014

Journal of Cell Science

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The dynamic interactions between cells and basement membranes serve as essential regulators of tissue architecture and function in metazoans, and perturbation of these interactions contributes to the progression of a wide range of human diseases, including cancers. Here, we reveal the pathway and mechanism for the endocytic trafficking of a prominent basement membrane protein, laminin-111 (referred to here as laminin), and their disruption in disease. Livecell imaging of epithelial cells revealed pronounced internalization of laminin into endocytic vesicles. Laminin internalization was receptor mediated and dynamin dependent, and laminin proceeded to the lysosome through the late endosome. Manipulation of laminin receptor expression revealed that the dominant regulator of laminin internalization is dystroglycan, a laminin receptor that is functionally perturbed in muscular dystrophies and in many cancers. Correspondingly, laminin internalization was found to be deficient in aggressive cancer cells displaying non-functional dystroglycan, and restoration of dystroglycan function strongly enhanced the endocytosis of laminin in both breast cancer and glioblastoma cells. These results establish previously unrecognized mechanisms for the modulation of cell-basement-membrane communication in normal cells and identify a profound disruption of endocytic laminin trafficking in aggressive cancer subtypes.

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Section: Discussionmentioning

confidence: 99%

Endocytic trafficking of laminin is controlled by dystroglycan and disrupted in cancers

Leonoudakis

Huang

Akhavan

et al. 2014

Journal of Cell Science

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“…Endocytosis plays a critical role in cancer development and treatment (Mellman and Yarden 2013). By mediating selective vesicular packaging of cell surface proteins, including receptors for growth factors, cytokines, and adhesion components, endocytosis regulates the levels of key cancer drivers by regulating their degradation in lysosomes or recycling back to the plasma membrane.…”

Section: Discussionmentioning

confidence: 99%

FBXL20-mediated Vps34 ubiquitination as a p53 controlled checkpoint in regulating autophagy and receptor degradation

Xiao

Zhang

et al. 2015

Genes Dev.

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Vacuolar protein-sorting 34 (Vps34), the catalytic subunit in the class III PtdIns3 (phosphatidylinositol 3) kinase complexes, mediates the production of PtdIns3P, a key intracellular lipid involved in regulating autophagy and receptor degradation. However, the signal transduction pathways by which extracellular signals regulate Vps34 complexes and the downstream cellular mechanisms are not well understood. Here we show that DNA damageactivated mitotic arrest and CDK activation lead to the phosphorylation of Vps34, which provides a signal to promote its ubiquitination and proteasomal degradation mediated by FBXL20 (an F-box protein) and the associated Skp1 (S-phase kinase-associated protein-1)-Cullin1 complex, leading to inhibition of autophagy and receptor endocytosis. Furthermore, we show that the expression of FBXL20 is regulated by p53-dependent transcription. Our study provides a molecular pathway by which DNA damage regulates Vps34 complexes and its downstream mechanisms, including autophagy and receptor endocytosis, through SCF (Skp1-Cul1-F-box)-mediated ubiquitination and degradation. Since the expression of FBXL20 is regulated by p53-dependent transcription, the control of Vps34 ubiquitination and proteasomal degradation by FBXL20 and the associated SCF complex expression provides a novel checkpoint for p53 to regulate autophagy and receptor degradation in DNA damage response.

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“…In cancer cells, p53 and RAS have been shown to modulate these endocytotic pathways. 4,20,39 Mutant forms of p53 or altered response to activated receptor tyrosine kinases may modulate the endocytotic response to low pO 2 . 4 …”

mentioning

confidence: 99%

Endocytotic uptake of HPMA-based polymers by different cancer cells: impact of extracellular acidosis and hypoxia

Gündel¹,

Allmeroth²,

Reime³

et al. 2017

IJN

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Background Polymeric nanoparticles allow to selectively transport chemotherapeutic drugs to the tumor tissue. These nanocarriers have to be taken up into the cells to release the drug. In addition, tumors often show pathological metabolic characteristics (hypoxia and acidosis) which might affect the polymer endocytosis. Materials and methods Six different N -(2-hydroxypropyl)methacrylamide (HPMA)-based polymer structures (homopolymer as well as random and block copolymers with lauryl methacrylate containing hydrophobic side chains) varying in molecular weight and size were analyzed in two different tumor models. The cellular uptake of fluorescence-labeled polymers was measured under hypoxic (pO 2 ≈1.5 mmHg) and acidic (pH 6.6) conditions. By using specific inhibitors, different endocytotic routes (macropinocytosis and clathrin-mediated, dynamin-dependent, cholesterol-dependent endocytosis) were analyzed separately. Results The current results revealed that the polymer uptake depends on the molecular structure, molecular weight and tumor line used. In AT1 cells, the uptake of random copolymer was five times stronger than the homopolymer, whereas in Walker-256 cells, the uptake of all polymers was much stronger, but this was independent of the molecular structure and size. Acidosis increased the uptake of random copolymer in AT1 cells but reduced the intracellular accumulation of homopolymer and block copolymer. Hypoxia reduced the uptake of all polymers in Walker-256 cells. Hydrophilic polymers (homopolymer and block copolymer) were taken up by all endocytotic routes studied, whereas the more lipophilic random copolymer seemed to be taken up preferentially by cholesterol- and dynamin-dependent endocytosis. Conclusion The study indicates that numerous parameters of the polymer (structure, size) and of the tumor (perfusion, vascular permeability, pH, pO 2 ) modulate drug delivery, which makes it difficult to select the appropriate polymer for the individual patient.

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Endocytosis and Cancer

Cited by 340 publications

References 174 publications

Endocytic trafficking of laminin is controlled by dystroglycan and disrupted in cancers

Endocytic trafficking of laminin is controlled by dystroglycan and disrupted in cancers

FBXL20-mediated Vps34 ubiquitination as a p53 controlled checkpoint in regulating autophagy and receptor degradation

Endocytotic uptake of HPMA-based polymers by different cancer cells: impact of extracellular acidosis and hypoxia

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