Targeting protein-trafficking pathways alters melanoma treatment sensitivity
- 27 December 2011
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 109 (2), 553-558
- https://doi.org/10.1073/pnas.1118366109
Abstract
Protein-trafficking pathways are targeted here in human melanoma cells using methods independent of oncogene mutational status, and the ability to up-regulate and down-regulate tumor treatment sensitivity is demonstrated. Sensitivity of melanoma cells to cis-diaminedichloroplatinum II (cDDP, cis-platin), carboplatin, dacarbazine, or temozolomide together with velaparib, an inhibitor of poly (ADP ribose) polymerase 1, is increased by up to 10-fold by targeting genes that regulate both protein trafficking and the formation of melanosomes, intracellular organelles unique to melanocytes and melanoma cells. Melanoma cells depleted of either of the protein-trafficking regulators vacuolar protein sorting 33A protein (VPS33A) or cappuccino protein (CNO) have increased nuclear localization of cDDP, increased nuclear DNA damage by platination, and increased apoptosis, resulting in increased treatment sensitivity. Depleted cells also exhibit a decreased proportion of intracellular, mature melanosomes compared with undepleted cells. Modulation of protein trafficking via cell-surface signaling by binding the melanocortin 1 receptor with the antagonist agouti-signaling protein decreased the proportion of mature melanosomes formed and increased cDDP sensitivity, whereas receptor binding with the agonist melanocyte-stimulating hormone resulted in an increased proportion of mature melanosomes formed and in decreased sensitivity (i.e., increased resistance) to cDDP. Mutation of the protein-trafficking gene Hps6, known to impair the formation of mature melanosomes, also increased cDDP sensitivity. Together, these results indicate that targeting protein-trafficking molecules markedly increases melanoma treatment sensitivity and influences the degree of melanosomes available for sequestration of therapeutic agents.This publication has 39 references indexed in Scilit:
- Improved Survival with Vemurafenib in Melanoma with BRAF V600E MutationThe New England Journal of Medicine, 2011
- Interactions between GIPC–APPL and GIPC–TRP1 regulate melanosomal protein trafficking and melanogenesis in human melanocytesArchives of Biochemistry and Biophysics, 2011
- An Integrated Approach to Uncover Drivers of CancerCell, 2010
- Loop-Swapped Chimeras of the Agouti-Related Protein and the Agouti Signaling Protein Identify Contacts Required for Melanocortin 1 Receptor Selectivity and AntagonismJournal of Molecular Biology, 2010
- Palmitoylated Ras proteins traffic through recycling endosomes to the plasma membrane during exocytosisThe Journal of cell biology, 2010
- Inhibition of transcription by platinum antitumor compoundsMetallomics, 2009
- Microarray analysis sheds light on the dedifferentiating role of agouti signal protein in murine melanocytes via the Mc1rProceedings of the National Academy of Sciences of the United States of America, 2009
- Inhibitors of melanogenesis increase toxicity of cyclophosphamide and lymphocytes against melanoma cellsInternational Journal of Cancer, 2008
- Melanosome Maturation Defect in Rab38-deficient Retinal Pigment Epithelium Results in Instability of Immature Melanosomes during Transient MelanogenesisMolecular Biology of the Cell, 2007
- Melanosomal sequestration of cytotoxic drugs contributes to the intractability of malignant melanomasProceedings of the National Academy of Sciences of the United States of America, 2006