Integrated proteomic profiling identifies amino acids selectively cytotoxic to pancreatic cancer cells
-
GRAPHICAL ABSTRACT
DownLoad:
Full size image
-
PUBLIC SUMMARY
- ■ Tumor cells exocytose amino acids via extracellular vesicles, which act as stressors to tumor cells.
- ■ Novel non-starvation approach using amino acids for treating pancreatic cancer.
- ■ Amino acid treatment is selective and effective against PDAC cells with no side effects.
- ■ The new treatment can be used as an adjuvant with chemotherapy to enhance efficacy.
-
ABSTRACT
Pancreatic adenocarcinoma (PDAC) is one of the most deadly cancers, characterized by extremely limited therapeutic options and a poor prognosis, as it is often diagnosed during late disease stages. Innovative and selective treatments are urgently needed, since current therapies have limited efficacy and significant side effects. Through proteomics analysis of extracellular vesicles, we discovered an imbalanced distribution of amino acids secreted by PDAC tumor cells. Our findings revealed that PDAC cells preferentially excrete proteins with certain preferential amino acids, including isoleucine and histidine, via extracellular vesicles. These amino acids are associated with disease progression and can be targeted to elicit selective toxicity to PDAC tumor cells. Both in vitro and in vivo experiments demonstrated that supplementation with these specific amino acids effectively eradicated PDAC cells. Mechanistically, we also identified XRN1 as a potential target for these amino acids. The high selectivity of this treatment method allows for specific targeting of tumor metabolism with very low toxicity to normal tissues. Furthermore, we found this treatment approach is easy-to-administer and with sustained tumor-killing effects. Together, our findings reveal that exocytosed amino acids may serve as therapeutic targets for designing treatments of intractable PDAC and potentially offer alternative treatments for other types of cancers. -
-
REFERENCES
[1] Lockhart, A.C., Rothenberg, M.L., and Berlin, J.D. (2005). Treatment for pancreatic cancer: Current therapy and continued progress. Gastroenterology 128(6): 1642-1654. [2] McGuigan, A., Kelly, P., Turkington, R.C., et al. (2018). Pancreatic cancer: A review of clinical diagnosis, epidemiology, treatment and outcomes. World J. Gastroenterol. 24(43): 4846-4861. [3] Pancreatic Cancer: Statistics | Cancer. Net (2019) (American Society of Clinical Oncology). https://www.cancer.net/cancer-types/pancreatic-cancer/statistics. [4] Kamisawa, T., Wood, L.D., Itoi, T., et al. (2016). Pancreatic cancer. Lancet 388(10039): 73-85. [5] Saung, M.T., and Zheng, L. (2017). Current standards of chemotherapy for pancreatic cancer. Clin. Therapeut. 39(11): 2125-2134. [6] Mallinson, C.N., Rake, M.O., Cocking, J.B., et al. (1980). Chemotherapy in pancreatic cancer: Results of a controlled, prospective, randomised, multicentre trial. Br. Med. J. 281(6255): 1589-1591. [7] Costa-Silva, B., Aiello, N.M., Ocean, A.J., et al. (2015). Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nat. Cell Biol. 17(6): 816-826. [8] Yu, C., Li, L., Liu, L., et al. (2022). Research of exosome in bone metastasis through dual aptamer recognition based entropy-driven amplification. Anal. Biochem. 636: 114433. https://doi.org/10.1016/j.ab.2021.114433. [9] Casari, I., Emmanouilidi, A., Domenichini, A., et al. (2022). Extracellular vesicles derived from pancreatic cancer cells are enriched in the growth factor Midkine. Adv. Biol. Regul. 83: 100857. https://doi.org/10.1016/j.jbior.2021.100857. [10] Arance, E., Ramírez, V., Rubio-Roldan, A., et al. (2021). Determination of exosome mitochondrial dna as a biomarker of renal cancer aggressiveness. Cancers 14(1): 199. [11] Wei, X.C., Liu, L.J., and Zhu, F. (2022). Exosomes as potential diagnosis and treatment for liver cancer. World J. Gastrointest. Oncol. 14(1): 334-347. [12] Yoshioka, Y., Kosaka, N., Konishi, Y., et al. (2014). Ultra-sensitive liquid biopsy of circulating extracellular vesicles using ExoScreen. Nat. Commun. 5: 3591. [13] Chow, A., Zhou, W., Liu, L., et al. (2014). Macrophage immunomodulation by breast cancer-derived exosomes requires Toll-like receptor 2-mediated activation of NF-κB. Sci. Rep. 4: 5750. [14] Melo, S.A., Luecke, L.B., Kahlert, C., et al. (2015). Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature 523(7559): 177-182. [15] Rasuleva, K., Elamurugan, S., Bauer, A., et al. (2021). β-sheet richness of the circulating tumor-derived extracellular vesicles for noninvasive pancreatic cancer screening. ACS Sens. 6(12): 4489-4498. [16] Xu, R., Yang, J., Ren, B., et al. (2020). Reprogramming of amino acid metabolism in pancreatic cancer: Recent advances and therapeutic strategies. Front. Oncol. 10: 572722. https://doi.org/10.3389/fonc.2020.572722. [17] Fauchon, M., Lagniel, G., Aude, J.C., et al. (2002). Sulfur sparing in the yeast proteome in response to sulfur demand. Mol. Cell. 9(4): 713-723. [18] Pashler, A.L., Towler, B.P., Jones, C.I., et al. (2016). The roles of the exoribonucleases DIS3L2 and XRN1 in disease. Biochem. Soc. Trans. 44(5): 1377-1384. [19] Ran, X.B., Ding, L.W., Sun, Q.Y., et al. (2023). Targeting RNA exonuclease XRN1 Potentiates Efficacy of Cancer Immunotherapy. Cancer Res. 83(6): 922-938. [20] Sun, D., Zhao, Z., Spiegel, S., et al. (2021). Dye-free spectrophotometric measurement of nucleic acid-to-protein ratio for cell-selective extracellular vesicle discrimination. Biosens. Bioelectron. 179: 113058. https://doi.org/10.1016/j.bios.2021.113058. [21] Colombo, M., Moita, C., van Niel, G., et al. (2013). Analysis of ESCRT functions in exosome biogenesis, composition and secretion highlights the heterogeneity of extracellular vesicles. J. Cell Sci. 126(Pt 24): 5553-5565. [22] Jones, S., Zhang, X., Parsons, D.W., et al. (2008). Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 321(5897): 1801-1806. [23] Qin, C., Yang, G., Yang, J., et al. (2020). Metabolism of pancreatic cancer: Paving the way to better anticancer strategies. Mol. Cancer 19(1): 50. [24] Biankin, A.V., Waddell, N., Kassahn, K.S., et al. (2012). Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature 491(7424): 399-405. [25] Kamphorst, J.J., Nofal, M., Commisso, C., et al. (2015). Human pancreatic cancer tumors are nutrient poor and tumor cells actively scavenge extracellular protein. Cancer Res. 75(3): 544-553. [26] Neinast, M.D., Jang, C., Hui, S., et al. (2019). Quantitative analysis of the whole-body metabolic fate of branched-chain amino acids. Cell Metabol. 29(2): 417-429. e4. [27] Wei, Z., Liu, X., Cheng, C., et al. (2020). Metabolism of amino acids in cancer. Front. Cell Dev. Biol. 8: 603837. https://doi.org/10.3389/fcell.2020.603837. [28] Conroy, T., Bachet, J.B., Ayav, A., et al. (2016). Current standards and new innovative approaches for treatment of pancreatic cancer. Eur. J. Cancer 57: 10-22. [29] Manji, G.A., Olive, K.P., Saenger, Y.M., et al. (2017). Current and emerging therapies in metastatic pancreatic cancer. Clin. Cancer Res. 23(7): 1670-1678. [30] Kanarek, N., Keys, H.R., Cantor, J.R., et al. (2018). Histidine catabolism is a major determinant of methotrexate sensitivity. Nature 559(7715): 632-636. [31] Gu, C., Mao, X., Chen, D., et al. (2019). Isoleucine plays an important role for maintaining immune function. Curr. Protein Pept. Sci. 20(7): 644-651. [32] Murata, K., and Moriyama, M. (2007). Isoleucine, an essential amino acid, prevents liver metastases of colon cancer by antiangiogenesis. Cancer Res. 67(7): 3263-3268. [33] Ciccolini, J., Serdjebi, C., Peters, G.J., et al. (2016). Pharmacokinetics and pharmacogenetics of Gemcitabine as a mainstay in adult and pediatric oncology: An EORTC-PAMM perspective. Cancer Chemother. Pharmacol. 78(1): 1-12. [34] Alberts, B., Johnson, A., Lewis, J., et al. (2002). Programmed Cell Death (Apoptosis). In Molecular Biology of the Cell, 4th edition (Garland Science). [35] Bastian, A., Thorpe, J.E., Disch, B.C., et al. (2015). A small molecule with anticancer and antimetastatic activities induces rapid mitochondrial-associated necrosis in breast cancer. J. Pharmacol. Exp. Therapeut. 353(2): 392-404. [36] Vyas, S., Zaganjor, E., and Haigis, M.C. (2016). Mitochondria and cancer. Cell 166(3): 555-566. [37] Gillespie, M., Jassal, B., Stephan, R., et al. (2022). The reactome pathway knowledgebase 2022. Nucleic Acids Res. 50(D1): D687-D692. [38] Bankhead, P., Loughrey, M.B., Fernández, J.A., et al. (2017). QuPath: Open source software for digital pathology image analysis. Sci. Rep. 7(1): 16878. https://doi.org/10.1038/s41598-017-17204-5. [39] Lieu, E.L., Nguyen, T., Rhyne, S., et al. (2020). Amino acids in cancer. Exp. Mol. Med. 52(1): 15-30. [40] Fung, M.K.L., and Chan, G.C.F. (2017). Drug-induced amino acid deprivation as strategy for cancer therapy. J. Hematol. Oncol. 10(1): 144. [41] Lind, D.S. (2004). Arginine and cancer. J. Nutr. 134(10): 2837S-2853S. [42] Choi, Y.K., and Park, K.G. (2018). Targeting glutamine metabolism for cancer treatment. Biomol. Ther. 26(1): 19-28. [43] Johnson, M.A., Vidoni, S., Durigon, R., et al. (2014). Amino acid starvation has opposite effects on mitochondrial and cytosolic protein synthesis. PLoS One 9(4): e93597. https://doi.org/10.1371/journal.pone.0093597. [44] Ragni, M., Fornelli, C., Nisoli, E., et al. (2022). Amino acids in cancer and cachexia: An integrated view. Cancers 14(22): 5691. [45] Cheng, X., Zhang, X., Cheng, W., et al. (2014). Tumor-specific delivery of histidine-rich glycoprotein suppresses tumor growth and metastasis by anti-angiogenesis and vessel normalization. Curr. Gene Ther. 14(2): 75-85. [46] Wang, H., Chen, S., Kang, W., et al. (2023). High dose isoleucine stabilizes nuclear PTEN to suppress the proliferation of lung cancer. Discov. Oncol. 14(1): 25. [47] Preciado, D., Moreno, G., Cardona, W., et al. (2022). Discovery of novel trihybrids based on salicylic acid/isoleucine/N-acylhydrazone: A promising therapeutic opportunity in colorectal cancer. J. Appl. Pharmaceut. Sci. 12(11): 10-20. [48] Blasco-Moreno, B., de Campos-Mata, L., Böttcher, R., et al. (2019). The exonuclease Xrn1 activates transcription and translation of mRNAs encoding membrane proteins. Nat. Commun. 10(1): 1298. [49] Akinlalu, A.O., Njoku, P.C., Nzekwe, C.V., et al. (2022). Recent developments in the significant effect of mRNA modification (M6A) in glioblastoma and esophageal cancer. Sci. Afr. 17: e01347. https://doi.org/10.1016/j.sciaf.2022.e01347. -
ABOUT THIS ARTICLE
Cite this article:
Akinlalu A., Flaten Z., Rasuleva K., et al., (2024). Integrated proteomic profiling identifies amino acids selectively cytotoxic to pancreatic cancer cells. The Innovation 5(3), 100626. https://doi.org/10.1016/j.xinn.2024.100626
Welcome!
To request copyright permission to republish or share portions of our works, please visit Copyright Clearance Center's (CCC) Marketplace website at marketplace.copyright.com.
Export File
Citation
Akinlalu A., Flaten Z., Rasuleva K., et al., (2024). Integrated proteomic profiling identifies amino acids selectively cytotoxic to pancreatic cancer cells. The Innovation 5(3), 100626. https://doi.org/10.1016/j.xinn.2024.100626
Format
Content
-
Figure 1.
PDAC cells selectively exocytose certain amino acids through EVs
-
Figure 2.
Histidine and isoleucine combination treatment is cytotoxic to PDAC cells with low side effects
-
Figure 3.
Synergistic combination of amino acids and gemcitabine enhances cytotoxicity to PDAC cells
-
Figure 4.
XRN1 is a target of the histidine and isoleucine metabolic pathway
-
Figure 5.
Amino acid treatment effectively impairs PDAC tumor growth and extends mice survival
