Extensive Unfolded Protein Response Stimulation in Colon Cancer Cells Enhances VEGF Expression and Secretion

Year 2020, , 329 - 343, 23.03.2020

Sinem Tunçer , Ege Solel Sreeparna Banerjee

https://doi.org/10.35193/bseufbd.631769

Cited By: 2

Abstract

Endoplasmic Reticulum (ER) is an important site
for protein folding and maturation. Accumulation of unfolded or misfolded
proteins in the ER leads to “ER stress”. The unfolded protein response (UPR) is
a finely regulated cell-signaling program to re-establish ER folding capacity
for building up cellular homeostasis. Although ER stress modulators have emerged
as promising treatment options with their potential to trigger ER
stress-mediated apoptosis in cancer cells, here we show that ER stress
upregulates VEGF (Vascular Endothelial Growth Factor) expression and secretion
in colon cancer cells, which may result in resistance against the treatment
through enhanced autocrine/intracrine VEGF signaling and through supporting
further angiogenesis.

Keywords

Colorectal cancer, VEGF, VEGFR, Unfolded Protein Response (UPR), ER stress

Thanks

Sinem Tunçer is supported by TÜBİTAK, 2218-National Postdoctoral Research Fellowship Program. The financial support of Banerjee Lab. is gratefully acknowledged. The authors would like to thank Aydan Torun for the technical support.

Kolon Kanseri Hücrelerinde Katlanmamış Protein Cevabının Aşırı Uyarılması VEGF İfadesini ve Salınımını Artırır

Abstract

Protein katlanması ve
olgunlaşması Endoplazmik Retikulum (ER)’da gerçekleşir. ER fonksiyonundaki
bozulmalar, yanlış katlanmış proteinlerin birikmesine neden olur ki bu durum
“ER stresi” olarak bilinir. Katlanmamış Protein Yanıtı (Unfolded Protein
Response-UPR), ER stresi durumunda hücresel homeostazın sağlanması için ER’de
protein katlanmasının yeniden ve doğrulukla gerçekleştirilmesi amacı ile
düzenlenmiş bir hücre sinyalizasyon programıdır. Bu çalışmada ER stresinin,
kolon kanseri hücrelerinde VEGF (Vascular Endothelial Growth Factor) ifadesini
ve VEGF’in hücre dışı salınımını arttırdığı gösterilmiştir. ER stresi modülatörleri
kanser hücrelerinde ER stresine bağlı apoptozisi tetikleme potansiyelleri ile
umut verici tedavi seçenekleri olarak sunulsa da, bu çalışma sonucu elde edilen
veriler, ER stresini tetikleyici yaklaşımların, artmış otokrin/intrakrin VEGF
sinyali ile tedaviye karşı dirence neden olabileceğini, hatta anjiyogenezi
destekleyebileceğini öne sürmektedir.

Keywords

Kolon kanseri, VEGF, VEGFR2, Katlanmamış Protein Yanıtı (UPR), ER stresi

References

• [1] Schaaf, M. B., Garg, A. D., & Agostinis, P. (2018). Defining the role of the tumor vasculature in antitumor immunity and immunotherapy. Cell Death Dis, 9(2), 115.
• [2] Yang, J., Yan, J., & Liu, B. (2018). Targeting VEGF/VEGFR to Modulate Antitumor Immunity. Front Immunol, 9, 978.
• [3] Peach, C. J., Mignone, V. W., Arruda, M. A., Alcobia, D. C., Hill, S. J., Kilpatrick, L. E., & Woolard, J. (2018). Molecular Pharmacology of VEGF-A Isoforms: Binding and Signalling at VEGFR2. Int J Mol Sci, 19(4).
• [4] Guzman-Hernandez, M. L., Potter, G., Egervari, K., Kiss, J. Z., & Balla, T. (2014). Secretion of VEGF-165 has unique characteristics, including shedding from the plasma membrane. Mol Biol Cell, 25(7), 1061-1072.
• [5] Dervenis, N., Mikropoulou, A. M., Tranos, P., & Dervenis, P. (2017). Ranibizumab in the Treatment of Diabetic Macular Edema: A Review of the Current Status, Unmet Needs, and Emerging Challenges. Adv Ther, 34(6), 1270-1282.
• [6] Shibuya, M. (2011). Vascular Endothelial Growth Factor (VEGF) and Its Receptor (VEGFR) Signaling in Angiogenesis: A Crucial Target for Anti- and Pro-Angiogenic Therapies. Genes Cancer, 2(12), 1097-1105.
• [7] Shibuya, M. (2010). Tyrosine Kinase Receptor Flt/VEGFR Family: Its Characterization Related to Angiogenesis and Cancer. Genes Cancer, 1(11), 1119-1123.
• [8] Pandey, A. K., Singhi, E. K., Arroyo, J. P., Ikizler, T. A., Gould, E. R., Brown, J., . . . Moslehi, J. (2018). Mechanisms of VEGF (Vascular Endothelial Growth Factor) Inhibitor-Associated Hypertension and Vascular Disease. Hypertension, 71(2), e1-e8.
• [9] Ahluwalia, A., Jones, M. K., Matysiak-Budnik, T., & Tarnawski, A. S. (2014). VEGF and colon cancer growth beyond angiogenesis: does VEGF directly mediate colon cancer growth via a non-angiogenic mechanism? Curr Pharm Des, 20(7), 1041-1044.
• [10] Yeh, C. C., Shih, L. J., Chang, J. L., Tsuei, Y. W., Wu, C. C., Hsiao, C. W., . . . Kao, Y. H. (2019). Synchronous vascular endothelial growth factor protein profiles in both tissue and serum identify metastasis and poor survival in colorectal cancer. Sci Rep, 9(1), 4228.
• [11] Bhattacharya, R., Ye, X. C., Wang, R., Ling, X., McManus, M., Fan, F., . . . Ellis, L. M. (2016). Intracrine VEGF Signaling Mediates the Activity of Prosurvival Pathways in Human Colorectal Cancer Cells. Cancer Res, 76(10), 3014-3024.
• [12] Zhang, Q., Yu, C., Peng, S., Xu, H., Wright, E., Zhang, X., . . . Souza, R. F. (2014). Autocrine VEGF signaling promotes proliferation of neoplastic Barrett's epithelial cells through a PLC-dependent pathway. Gastroenterology, 146(2), 461-472 e466.
• [13] Santos, S. C., & Dias, S. (2004). Internal and external autocrine VEGF/KDR loops regulate survival of subsets of acute leukemia through distinct signaling pathways. Blood, 103(10), 3883-3889.
• [14] Lichtenberger, B. M., Tan, P. K., Niederleithner, H., Ferrara, N., Petzelbauer, P., & Sibilia, M. (2010). Autocrine VEGF signaling synergizes with EGFR in tumor cells to promote epithelial cancer development. Cell, 140(2), 268-279.
• [15] Ohba, T., Cates, J. M., Cole, H. A., Slosky, D. A., Haro, H., Ando, T., . . . Schoenecker, J. G. (2014). Autocrine VEGF/VEGFR1 signaling in a subpopulation of cells associates with aggressive osteosarcoma. Mol Cancer Res, 12(8), 1100-1111.
• [16] Barr, M. P., Gray, S. G., Gately, K., Hams, E., Fallon, P. G., Davies, A. M., . . . O'Byrne, K. J. (2015). Vascular endothelial growth factor is an autocrine growth factor, signaling through neuropilin-1 in non-small cell lung cancer. Mol Cancer, 14, 45.
• [17] Masood, R., Cai, J., Zheng, T., Smith, D. L., Hinton, D. R., & Gill, P. S. (2001). Vascular endothelial growth factor (VEGF) is an autocrine growth factor for VEGF receptor-positive human tumors. Blood, 98(6), 1904-1913.
• [18] Corazzari, M., Gagliardi, M., Fimia, G. M., & Piacentini, M. (2017). Endoplasmic Reticulum Stress, Unfolded Protein Response, and Cancer Cell Fate. Front Oncol, 7, 78.
• [19] Sisinni, L., Pietrafesa, M., Lepore, S., Maddalena, F., Condelli, V., Esposito, F., & Landriscina, M. (2019). Endoplasmic Reticulum Stress and Unfolded Protein Response in Breast Cancer: The Balance between Apoptosis and Autophagy and Its Role in Drug Resistance. Int J Mol Sci, 20(4).
• [20] Poplawski, T., Pytel, D., Dziadek, J., & Majsterek, I. (2019). Interplay between Redox Signaling, Oxidative Stress, and Unfolded Protein Response (UPR) in Pathogenesis of Human Diseases. Oxid Med Cell Longev, 2019, 6949347.
• [21] Wang, M., Law, M. E., Castellano, R. K., & Law, B. K. (2018). The unfolded protein response as a target for anticancer therapeutics. Crit Rev Oncol Hematol, 127, 66-79.
• [22] Pfaffl, M. W. (2001). A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res, 29(9), e45.
• [23] Bustin, S. A., Benes, V., Garson, J. A., Hellemans, J., Huggett, J., Kubista, M., . . . Wittwer, C. T. (2009). The MIQE guidelines: minimum information for publication of quantitative real-time PCR experiments. Clin Chem, 55(4), 611-622.
• [24] Aldebasi, Y. H., Rahmani, A. H., Khan, A. A., & Aly, S. M. (2013). The effect of vascular endothelial growth factor in the progression of bladder cancer and diabetic retinopathy. Int J Clin Exp Med, 6(4), 239-251.
• [25] Podar, K., & Anderson, K. C. (2005). The pathophysiologic role of VEGF in hematologic malignancies: therapeutic implications. Blood, 105(4), 1383-1395.
• [26] Ratnasari, N. & Yano, Y. (2015). “Do Soluble Vascular Endothelial Growth Factor and Its Receptors Predict the Progression of Chronic Hepatitis to Hepatocellular Carcinoma ?,” J. Hepat., no. Il, pp. 2–5.
• [27] Liu, Y., Feng, J., Zhao, M., Wu, J., Fan, J., Wen, Q., . . . Yang, L. (2017). JNK pathway inhibition enhances chemotherapeutic sensitivity to Adriamycin in nasopharyngeal carcinoma cells. Oncol Lett, 14(2), 1790-1794.
• [28] Shen, M., Wang, L., Guo, X., Xue, Q., Huo, C., Li, X., . . . Wang, X. (2015). A novel endoplasmic reticulum stressinduced apoptosis model using tunicamycin in primary cultured neonatal rat cardiomyocytes. Mol Med Rep, 12(4), 5149-5154.
• [29] Oslowski, C. M., & Urano, F. (2011). Measuring ER stress and the unfolded protein response using mammalian tissue culture system. Methods Enzymol, 490, 71-92.
• [30] Berridge, M. J., Lipp, P., & Bootman, M. D. (2000). The versatility and universality of calcium signalling. Nat Rev Mol Cell Biol, 1(1), 11-21.
• [31] Mendez, J. M., Kolora, L. D., Lemon, J. S., Dupree, S. L., & Keestra-Gounder, A. M. (2019). Activation of the Endoplasmic Reticulum Stress Response Impacts the NOD1 Signaling Pathway. Infect Immun, 87(8).
• [32] Wie, M. B., Koh, J. Y., Won, M. H., Lee, J. C., Shin, T. K., Moon, C. J., . . . Kim, H. C. (2001). BAPTA/AM, an intracellular calcium chelator, induces delayed necrosis by lipoxygenase-mediated free radicals in mouse cortical cultures. Prog Neuropsychopharmacol Biol Psychiatry, 25(8), 1641-1659.
• [33] Ferrara, N. (2004). Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev, 25(4), 581-611.
• [34] Bendardaf, R., Buhmeida, A., Hilska, M., Laato, M., Syrjanen, S., Syrjanen, K., . . . Pyrhonen, S. (2008). VEGF-1 expression in colorectal cancer is associated with disease localization, stage, and long-term disease-specific survival. Anticancer Res, 28(6B), 3865-3870.
• [35] Bendardaf, R., El-Serafi, A., Syrjanen, K., Collan, Y., & Pyrhonen, S. (2017). The effect of vascular endothelial growth factor-1 expression on survival of advanced colorectal cancer patients. Libyan J Med, 12(1), 1290741.
• [36] Lee, T. H., Seng, S., Sekine, M., Hinton, C., Fu, Y., Avraham, H. K., & Avraham, S. (2007). Vascular endothelial growth factor mediates intracrine survival in human breast carcinoma cells through internally expressed VEGFR1/FLT1. PLoS Med, 4(6), e186.
• [37] Hammond, W. A., Swaika, A., & Mody, K. (2016). Pharmacologic resistance in colorectal cancer: a review. Ther Adv Med Oncol, 8(1), 57-84.
• [38] Liu, X., Zhao, P., Wang, X., Wang, L., Zhu, Y., & Gao, W. (2019). Triptolide Induces Glioma Cell Autophagy and Apoptosis via Upregulating the ROS/JNK and Downregulating the Akt/mTOR Signaling Pathways. Front Oncol, 9, 387.
• [39] Bahar, E., Kim, J. Y., & Yoon, H. (2019). Chemotherapy Resistance Explained through Endoplasmic Reticulum Stress-Dependent Signaling. Cancers (Basel), 11(3).
• [40] Al-Abd, A. M., Alamoudi, A. J., Abdel-Naim, A. B., Neamatallah, T. A., & Ashour, O. M. (2017). Anti-angiogenic agents for the treatment of solid tumors: Potential pathways, therapy and current strategies - A review. J Adv Res, 8(6), 591-605.