Use of Small-molecule Inhibitory Compound of PERK-dependent Signaling Pathway as a Promising Target-based Therapy for Colorectal Cancer

Author(s): Wioletta Rozpędek, Dariusz Pytel, Adam Wawrzynkiewicz, Natalia Siwecka, Adam Dziki, Łukasz Dziki, J. Alan Diehl, Ireneusz Majsterek*

Journal Name: Current Cancer Drug Targets

Volume 20 , Issue 3 , 2020

  Journal Home
Translate in Chinese
Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Background: Colorectal cancer constitutes one of the most common cancer with a high mortality rate. The newest data has reported that activation of the pro-apoptotic PERK-dependent unfolded protein response signaling pathway by small-molecule inhibitors may constitute an innovative anti-cancer treatment strategy.

Objective: In the presented study, we evaluated the effectiveness of the PERK-dependent unfolded protein response signaling pathway small-molecule inhibitor 42215 both on HT-29 human colon adenocarcinoma and CCD 841 CoN normal human colon epithelial cell lines.

Methods: Cytotoxicity of the PERK inhibitor was evaluated by the resazurin-based and lactate dehydrogenase (LDH) tests. Apoptotic cell death was measured by flow cytometry using the FITCconjugated Annexin V to indicate apoptosis and propidium iodide to indicate necrosis as well as by colorimetric caspase-3 assay. The effect of tested PERK inhibitor on cell cycle progression was measured by flow cytometry using the propidium iodide staining. The level of the phosphorylated form of the eukaryotic initiation factor 2 alpha was detected by the Western blot technique.

Results: Obtained results showed that investigated PERK inhibitor is selective only toward cancer cells, since inhibited their viability in a dose- and time-dependent manner and induced their apoptosis and G2/M cell cycle arrest. Furthermore, 42215 PERK inhibitor evoked significant inhibition of eIF2α phosphorylation within HT-29 cancer cells.

Conclusion: Highly-selective PERK inhibitors may provide a ground-breaking, anti-cancer treatment strategy via activation of the pro-apoptotic branch of the PERK-dependent unfolded protein response signaling pathway.

Keywords: PERK, eIF2α, PERK inhibitor, endoplasmic reticulum stress, unfolded protein response, cancer, apoptosis.

[1]
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2018. CA Cancer J. Clin., 2018, 68(1), 7-30.
[http://dx.doi.org/10.3322/caac.21442] [PMID: 29313949]
[2]
Cooper, G.M. The cell: a molecular approach, 2nd ed; ASM Press Sinauer Associates: Washington, D.C. Sunderland, Massachusetts, 2000.
[3]
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer Statistics, 2017. CA Cancer J. Clin., 2017, 67(1), 7-30.
[http://dx.doi.org/10.3322/caac.21387] [PMID: 28055103]
[4]
Arnold, M.; Sierra, M.S.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global patterns and trends in colorectal cancer incidence and mortality. Gut, 2017, 66(4), 683-691.
[http://dx.doi.org/10.1136/gutjnl-2015-310912] [PMID: 26818619]
[5]
Favoriti, P.; Carbone, G.; Greco, M.; Pirozzi, F.; Pirozzi, R.E.; Corcione, F. Worldwide burden of colorectal cancer: A review. Updates Surg., 2016, 68(1), 7-11.
[http://dx.doi.org/10.1007/s13304-016-0359-y] [PMID: 27067591]
[6]
Li, X.; An, B.; Ma, J.; He, B.; Qi, J.; Wang, W.; Qin, C.; Zhao, Q. Prognostic value of the tumor size in resectable colorectal cancer with different primary locations: A retrospective study with the propensity score matching. J. Cancer, 2019, 10(2), 313-322.
[http://dx.doi.org/10.7150/jca.26882] [PMID: 30719125]
[7]
Kanwar, S.S.; Poolla, A.; Majumdar, A.P. Regulation of colon cancer recurrence and development of therapeutic strategies. World J. Gastrointest. Pathophysiol., 2012, 3(1), 1-9.
[http://dx.doi.org/10.4291/wjgp.v3.i1.1] [PMID: 22368781]
[8]
Zou, H.; Li, L.; Garcia Carcedo, I.; Xu, Z.P.; Monteiro, M.; Gu, W. Synergistic inhibition of colon cancer cell growth with nanoemulsion-loaded paclitaxel and PI3K/mTOR dual inhibitor BEZ235 through apoptosis. Int. J. Nanomedicine, 2016, 11, 1947-1958.
[PMID: 27226714]
[9]
Jemal, A.; Clegg, L.X.; Ward, E.; Ries, L.A.; Wu, X.; Jamison, P.M.; Wingo, P.A.; Howe, H.L.; Anderson, R.N.; Edwards, B.K. Annual report to the nation on the status of cancer, 1975-2001, with a special feature regarding survival. Cancer, 2004, 101(1), 3-27.
[http://dx.doi.org/10.1002/cncr.20288] [PMID: 15221985]
[10]
Muz, B.; de la Puente, P.; Azab, F.; Azab, A.K. The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy. Hypoxia (Auckl.), 2015, 3, 83-92.
[http://dx.doi.org/10.2147/HP.S93413] [PMID: 27774485]
[11]
Liu, C.Y.; Kaufman, R.J. The unfolded protein response. J. Cell Sci., 2003, 116(Pt 10), 1861-1862.
[http://dx.doi.org/10.1242/jcs.00408] [PMID: 12692187]
[12]
Pereira, E.R.; Frudd, K.; Awad, W.; Hendershot, L.M. Endoplasmic reticulum (ER) stress and hypoxia response pathways interact to potentiate hypoxia-inducible factor 1 (HIF-1) transcriptional activity on targets like vascular endothelial growth factor (VEGF). J. Biol. Chem., 2014, 289(6), 3352-3364.
[http://dx.doi.org/10.1074/jbc.M113.507194] [PMID: 24347168]
[13]
Koumenis, C. ER stress, hypoxia tolerance and tumor progression. Curr. Mol. Med., 2006, 6(1), 55-69.
[http://dx.doi.org/10.2174/156652406775574604] [PMID: 16472113]
[14]
Siwecka, N.; Rozpędek, W.; Pytel, D.; Wawrzynkiewicz, A.; Dziki, A.; Dziki, Ł.; Diehl, J.A.; Majsterek, I. Dual role of endoplasmic reticulum stress-mediated unfolded protein response signaling pathway in carcinogenesis. Int. J. Mol. Sci., 2019, 20(18), E4354
[http://dx.doi.org/10.3390/ijms20184354] [PMID: 31491919]
[15]
Rozpedek, W.; Nowak, A.; Pytel, D.; Diehl, J.A.; Majsterek, I. Molecular basis of human diseases and targeted therapy based on small-molecule inhibitors of ER stress-induced signaling pathways. Curr. Mol. Med., 2017, 17(2), 118-132.
[http://dx.doi.org/10.2174/1566524017666170306122643] [PMID: 28266275]
[16]
Madden, E.; Logue, S.E.; Healy, S.J.; Manie, S.; Samali, A. The role of the unfolded protein response in cancer progression: From oncogenesis to chemoresistance. Biol. Cell, 2019, 111(1), 1-17.
[http://dx.doi.org/10.1111/boc.201800050] [PMID: 30302777]
[17]
Ojha, R.; Amaravadi, R.K. Targeting the unfolded protein response in cancer. Pharmacol. Res., 2017, 120, 258-266.
[http://dx.doi.org/10.1016/j.phrs.2017.04.003] [PMID: 28396092]
[18]
Ma, Y.; Hendershot, L.M. The role of the unfolded protein response in tumour development: Friend or foe? Nat. Rev. Cancer, 2004, 4(12), 966-977.
[http://dx.doi.org/10.1038/nrc1505] [PMID: 15573118]
[19]
Bobrovnikova-Marjon, E.; Grigoriadou, C.; Pytel, D.; Zhang, F.; Ye, J.; Koumenis, C.; Cavener, D.; Diehl, J.A. PERK promotes cancer cell proliferation and tumor growth by limiting oxidative DNA damage. Oncogene, 2010, 29(27), 3881-3895.
[http://dx.doi.org/10.1038/onc.2010.153] [PMID: 20453876]
[20]
Wang, W.A.; Groenendyk, J.; Michalak, M. Endoplasmic reticulum stress associated responses in cancer. Biochim. Biophys. Acta, 2014, 1843(10), 2143-2149.
[http://dx.doi.org/10.1016/j.bbamcr.2014.01.012] [PMID: 24440276]
[21]
Limonta, P.; Moretti, R.M.; Marzagalli, M.; Fontana, F.; Raimondi, M.; Montagnani Marelli, M. Role of endoplasmic reticulum stress in the anticancer activity of natural compounds. Int. J. Mol. Sci., 2019, 20(4), E961
[http://dx.doi.org/10.3390/ijms20040961] [PMID: 30813301]
[22]
Rozpedek, W.; Pytel, D.; Mucha, B.; Leszczynska, H.; Diehl, J.A.; Majsterek, I. The role of the PERK/eIF2α/ATF4/CHOP signaling pathway in tumor progression during endoplasmic reticulum stress. Curr. Mol. Med., 2016, 16(6), 533-544.
[http://dx.doi.org/10.2174/1566524016666160523143937] [PMID: 27211800]
[23]
Hu, H.; Tian, M.; Ding, C.; Yu, S. The C/EBP homologous protein (CHOP) transcription factor functions in endoplasmic reticulum stress-induced apoptosis and microbial infection. Front. Immunol., 2019, 9, 3083.
[http://dx.doi.org/10.3389/fimmu.2018.03083] [PMID: 30662442]
[24]
Lei, Y.; Wang, S.; Ren, B.; Wang, J.; Chen, J.; Lu, J.; Zhan, S.; Fu, Y.; Huang, L.; Tan, J. CHOP favors endoplasmic reticulum stress-induced apoptosis in hepatocellular carcinoma cells via inhibition of autophagy. PLoS One, 2017, 12(8), e0183680
[http://dx.doi.org/10.1371/journal.pone.0183680] [PMID: 28841673]
[25]
Oka, O.B.; Bulleid, N.J. Forming disulfides in the endoplasmic reticulum. Biochim. Biophys. Acta, 2013, 1833(11), 2425-2429.
[http://dx.doi.org/10.1016/j.bbamcr.2013.02.007] [PMID: 23434683]
[26]
Grek, C.; Townsend, D.M. Protein disulfide isomerase superfamily in disease and the regulation of apoptosis. Endoplasmic Reticulum Stress Dis., 2014, 1(1), 4-17.
[http://dx.doi.org/10.2478/ersc-2013-0001] [PMID: 25309899]
[27]
Hsu, S.K.; Chiu, C.C.; Dahms, H.U.; Chou, C.K.; Cheng, C.M.; Chang, W.T.; Cheng, K.C.; Wang, H.D.; Lin, I.L. Unfolded protein response (UPR) in survival, dormancy, immunosuppression, metastasis, and treatments of cancer cells. Int. J. Mol. Sci., 2019, 20(10), E2518
[http://dx.doi.org/10.3390/ijms20102518] [PMID: 31121863]
[28]
Takei, N.; Yoneda, A.; Sakai-Sawada, K.; Kosaka, M.; Minomi, K.; Tamura, Y. Hypoxia-inducible ERO1α promotes cancer progression through modulation of integrin-β1 modification and signalling in HCT116 colorectal cancer cells. Sci. Rep., 2017, 7(1), 9389.
[http://dx.doi.org/10.1038/s41598-017-09976-7] [PMID: 28839225]
[29]
Pytel, D.; Seyb, K.; Liu, M.; Ray, S.S.; Concannon, J.; Huang, M.; Cuny, G.D.; Diehl, J.A.; Glicksman, M.A. Enzymatic characterization of ER stress-dependent kinase, PERK, and development of a high-throughput assay for identification of PERK inhibitors. J. Biomol. Screen., 2014, 19(7), 1024-1034.
[http://dx.doi.org/10.1177/1087057114525853] [PMID: 24598103]
[30]
Agarwal, M.B. Is cancer chemotherapy dying? Asian J. Transfus. Sci., 2016, 10(Suppl. 1), S1-S7.
[http://dx.doi.org/10.4103/0973-6247.182735] [PMID: 27330251]
[31]
Naveed, S.; Aslam, M.; Ahmad, A. Starvation based differential chemotherapy: A novel approach for cancer treatment. Oman Med. J., 2014, 29(6), 391-398.
[http://dx.doi.org/10.5001/omj.2014.107] [PMID: 25584154]
[32]
Partridge, A.H.; Burstein, H.J.; Winer, E.P. Side effects of chemotherapy and combined chemohormonal therapy in women with early-stage breast cancer. J. Natl. Cancer Inst. Monogr., 2001, (30), 135-142.
[http://dx.doi.org/10.1093/oxfordjournals.jncimonographs.a003451] [PMID: 11773307]
[33]
Nurgali, K.; Jagoe, R.T.; Abalo, R. Editorial: Adverse effects of cancer chemotherapy: Anything new to improve tolerance and reduce sequelae? Front. Pharmacol., 2018, 9, 245.
[http://dx.doi.org/10.3389/fphar.2018.00245] [PMID: 29623040]
[34]
Karolak, A.; Estrella, V.C.; Huynh, A.S.; Chen, T.; Vagner, J.; Morse, D.L.; Rejniak, K.A. Targeting ligand specificity linked to tumor tissue topological heterogeneity via single-cell micro-pharmacological modeling. Sci. Rep., 2018, 8(1), 3638.
[http://dx.doi.org/10.1038/s41598-018-21883-z] [PMID: 29483578]
[35]
Shi, Z.; Yu, X.; Yuan, M.; Lv, W.; Feng, T.; Bai, R.; Zhong, H. Activation of the PERK-ATF4 pathway promotes chemo-resistance in colon cancer cells. Sci. Rep., 2019, 9(1), 3210.
[http://dx.doi.org/10.1038/s41598-019-39547-x] [PMID: 30824833]
[36]
Salaroglio, I.C.; Panada, E.; Moiso, E.; Buondonno, I.; Provero, P.; Rubinstein, M.; Kopecka, J.; Riganti, C. PERK induces resistance to cell death elicited by endoplasmic reticulum stress and chemotherapy. Mol. Cancer, 2017, 16(1), 91.
[http://dx.doi.org/10.1186/s12943-017-0657-0] [PMID: 28499449]
[37]
Chipurupalli, S.; Kannan, E.; Tergaonkar, V.; D’Andrea, R.; Robinson, N. Hypoxia induced ER stress response as an adaptive mechanism in cancer. Int. J. Mol. Sci., 2019, 20(3), E749
[http://dx.doi.org/10.3390/ijms20030749] [PMID: 30754624]
[38]
Dauer, P.; Sharma, N.S.; Gupta, V.K.; Durden, B.; Hadad, R.; Banerjee, S.; Dudeja, V.; Saluja, A.; Banerjee, S. ER stress sensor, glucose regulatory protein 78 (GRP78) regulates redox status in pancreatic cancer thereby maintaining “stemness”. Cell Death Dis., 2019, 10(2), 132.
[http://dx.doi.org/10.1038/s41419-019-1408-5] [PMID: 30755605]
[39]
Deng, W.G.; Ruan, K.H.; Du, M.; Saunders, M.A.; Wu, K.K. Aspirin and salicylate bind to immunoglobulin heavy chain binding protein (BiP) and inhibit its ATPase activity in human fibroblasts. FASEB J., 2001, 15(13), 2463-2470.
[http://dx.doi.org/10.1096/fj.01-0259com] [PMID: 11689471]
[40]
Sharma, S.H.; Rajamanickam, V.; Nagarajan, S. Antiproliferative effect of p-Coumaric acid targets UPR activation by downregulating Grp78 in colon cancer. Chem. Biol. Interact., 2018, 291, 16-28.
[http://dx.doi.org/10.1016/j.cbi.2018.06.001] [PMID: 29879413]
[41]
Rouschop, K.M.; Dubois, L.J.; Keulers, T.G.; van den Beucken, T.; Lambin, P.; Bussink, J.; van der Kogel, A.J.; Koritzinsky, M.; Wouters, B.G. PERK/eIF2α signaling protects therapy resistant hypoxic cells through induction of glutathione synthesis and protection against ROS. Proc. Natl. Acad. Sci. USA, 2013, 110(12), 4622-4627.
[http://dx.doi.org/10.1073/pnas.1210633110] [PMID: 23471998]
[42]
Armengol, G.; Rojo, F.; Castellví, J.; Iglesias, C.; Cuatrecasas, M.; Pons, B.; Baselga, J.; Ramón y Cajal, S. 4E-binding protein 1: A key molecular “funnel factor” in human cancer with clinical implications. Cancer Res., 2007, 67(16), 7551-7555.
[http://dx.doi.org/10.1158/0008-5472.CAN-07-0881] [PMID: 17699757]
[43]
Larsson, O.; Li, S.; Issaenko, O.A.; Avdulov, S.; Peterson, M.; Smith, K.; Bitterman, P.B.; Polunovsky, V.A. Eukaryotic translation initiation factor 4E induced progression of primary human mammary epithelial cells along the cancer pathway is associated with targeted translational deregulation of oncogenic drivers and inhibitors. Cancer Res., 2007, 67(14), 6814-6824.
[http://dx.doi.org/10.1158/0008-5472.CAN-07-0752] [PMID: 17638893]
[44]
Pervin, S.; Tran, A.H.; Zekavati, S.; Fukuto, J.M.; Singh, R.; Chaudhuri, G. Increased susceptibility of breast cancer cells to stress mediated inhibition of protein synthesis. Cancer Res., 2008, 68(12), 4862-4874.
[http://dx.doi.org/10.1158/0008-5472.CAN-08-0074] [PMID: 18559534]
[45]
Blais, J.D.; Addison, C.L.; Edge, R.; Falls, T.; Zhao, H.; Wary, K.; Koumenis, C.; Harding, H.P.; Ron, D.; Holcik, M.; Bell, J.C. Perk-dependent translational regulation promotes tumor cell adaptation and angiogenesis in response to hypoxic stress. Mol. Cell. Biol., 2006, 26(24), 9517-9532.
[http://dx.doi.org/10.1128/MCB.01145-06] [PMID: 17030613]
[46]
Giglio, P.; Fimia, G.M.; Lovat, P.E.; Piacentini, M.; Corazzari, M. Fateful music from a talented orchestra with a wicked conductor: Connection between oncogenic BRAF, ER stress, and autophagy in human melanoma. Mol. Cell. Oncol., 2015, 2(3), e995016
[http://dx.doi.org/10.4161/23723556.2014.995016] [PMID: 27308477]
[47]
Corazzari, M.; Rapino, F.; Ciccosanti, F.; Giglio, P.; Antonioli, M.; Conti, B.; Fimia, G.M.; Lovat, P.E.; Piacentini, M. Oncogenic BRAF induces chronic ER stress condition resulting in increased basal autophagy and apoptotic resistance of cutaneous melanoma. Cell Death Differ., 2015, 22(6), 946-958.
[http://dx.doi.org/10.1038/cdd.2014.183] [PMID: 25361077]
[48]
Corazzari, M.; Gagliardi, M.; Fimia, G.M.; Piacentini, M. Endoplasmic reticulum stress, unfolded protein response, and cancer cell fate. Front. Oncol., 2017, 7, 78.
[http://dx.doi.org/10.3389/fonc.2017.00078] [PMID: 28491820]
[49]
Wouters, B.G.; van den Beucken, T.; Magagnin, M.G.; Lambin, P.; Koumenis, C. Targeting hypoxia tolerance in cancer. Drug Resist. Updat., 2004, 7(1), 25-40.
[http://dx.doi.org/10.1016/j.drup.2003.12.004] [PMID: 15072769]
[50]
Schito, L.; Semenza, G.L. Hypoxia-inducible factors: Master regulators of cancer progression. Trends Cancer, 2016, 2(12), 758-770.
[http://dx.doi.org/10.1016/j.trecan.2016.10.016] [PMID: 28741521]
[51]
Petrova, V.; Annicchiarico-Petruzzelli, M.; Melino, G.; Amelio, I. The hypoxic tumour microenvironment. Oncogenesis, 2018, 7(1), 10.
[http://dx.doi.org/10.1038/s41389-017-0011-9] [PMID: 29362402]
[52]
Rozpedek, W.; Pytel, D.; Nowak-Zdunczyk, A.; Lewko, D.; Wojtczak, R.; Diehl, J.A.; Majsterek, I. Breaking the DNA damage response via serine/threonine kinase inhibitors to improve cancer treatment. Curr. Med. Chem., 2018.
[PMID: 29345572]
[53]
Koumenis, C.; Naczki, C.; Koritzinsky, M.; Rastani, S.; Diehl, A.; Sonenberg, N.; Koromilas, A.; Wouters, B.G. Regulation of protein synthesis by hypoxia via activation of the endoplasmic reticulum kinase PERK and phosphorylation of the translation initiation factor eIF2alpha. Mol. Cell. Biol., 2002, 22(21), 7405-7416.
[http://dx.doi.org/10.1128/MCB.22.21.7405-7416.2002] [PMID: 12370288]
[54]
Höckel, M.; Vaupel, P. Tumor hypoxia: Definitions and current clinical, biologic, and molecular aspects. J. Natl. Cancer Inst., 2001, 93(4), 266-276.
[http://dx.doi.org/10.1093/jnci/93.4.266] [PMID: 11181773]
[55]
Li, Z.; Li, Z. Glucose regulated protein 78: A critical link between tumor microenvironment and cancer hallmarks. Biochim. Biophys. Acta, 2012, 1826(1), 13-22.
[PMID: 22426159]
[56]
Shuda, M.; Kondoh, N.; Imazeki, N.; Tanaka, K.; Okada, T.; Mori, K.; Hada, A.; Arai, M.; Wakatsuki, T.; Matsubara, O.; Yamamoto, N.; Yamamoto, M. Activation of the ATF6, XBP1 and grp78 genes in human hepatocellular carcinoma: A possible involvement of the ER stress pathway in hepatocarcinogenesis. J. Hepatol., 2003, 38(5), 605-614.
[http://dx.doi.org/10.1016/S0168-8278(03)00029-1] [PMID: 12713871]
[57]
Li, J.; Lee, A.S. Stress induction of GRP78/BiP and its role in cancer. Curr. Mol. Med., 2006, 6(1), 45-54.
[http://dx.doi.org/10.2174/156652406775574523] [PMID: 16472112]
[58]
Fu, Y.; Li, J.; Lee, A.S. GRP78/BiP inhibits endoplasmic reticulum BIK and protects human breast cancer cells against estrogen starvation-induced apoptosis. Cancer Res., 2007, 67(8), 3734-3740.
[http://dx.doi.org/10.1158/0008-5472.CAN-06-4594] [PMID: 17440086]
[59]
Song, M.S.; Park, Y.K.; Lee, J.H.; Park, K. Induction of glucose-regulated protein 78 by chronic hypoxia in human gastric tumor cells through a protein kinase C-epsilon/ERK/AP-1 signaling cascade. Cancer Res., 2001, 61(22), 8322-8330.
[PMID: 11719466]
[60]
Zorzi, E.; Bonvini, P. Inducible hsp70 in the regulation of cancer cell survival: Analysis of chaperone induction, expression and activity. Cancers (Basel), 2011, 3(4), 3921-3956.
[http://dx.doi.org/10.3390/cancers3043921] [PMID: 24213118]
[61]
Miao, Y.R.; Eckhardt, B.L.; Cao, Y.; Pasqualini, R.; Argani, P.; Arap, W.; Ramsay, R.G.; Anderson, R.L. Inhibition of established micrometastases by targeted drug delivery via cell surface-associated GRP78. Clin. Cancer Res., 2013, 19(8), 2107-2116.
[http://dx.doi.org/10.1158/1078-0432.CCR-12-2991] [PMID: 23470966]
[62]
Mhaidat, N.M.; Alzoubi, K.H.; Almomani, N.; Khabour, O.F. Expression of glucose regulated protein 78 (GRP78) determines colorectal cancer response to chemotherapy. Cancer Biomark., 2015, 15(2), 197-203.
[http://dx.doi.org/10.3233/CBM-140454] [PMID: 25519021]
[63]
Mhaidat, N.M.; Alzoubi, K.H.; Khabour, O.F.; Banihani, M.N.; Al-Balas, Q.A.; Swaidan, S. GRP78 regulates sensitivity of human colorectal cancer cells to DNA targeting agents. Cytotechnology, 2016, 68(3), 459-467.
[http://dx.doi.org/10.1007/s10616-014-9799-8] [PMID: 25399254]
[64]
Pi, L.; Li, X.; Song, Q.; Shen, Y.; Lu, X.; Di, B. Knockdown of glucose-regulated protein 78 abrogates chemoresistance of hypopharyngeal carcinoma cells to cisplatin induced by unfolded protein in response to severe hypoxia. Oncol. Lett., 2014, 7(3), 685-692.
[http://dx.doi.org/10.3892/ol.2013.1753] [PMID: 24527073]
[65]
Chang, Y.J.; Chen, W.Y.; Huang, C.Y.; Liu, H.H.; Wei, P.L. Glucose-regulated protein 78 (GRP78) regulates colon cancer metastasis through EMT biomarkers and the NRF-2/HO-1 pathway. Tumour Biol., 2015, 36(3), 1859-1869.
[http://dx.doi.org/10.1007/s13277-014-2788-x] [PMID: 25431258]
[66]
Chern, Y.J.; Wong, J.C.T.; Cheng, G.S.W.; Yu, A.; Yin, Y.; Schaeffer, D.F.; Kennecke, H.F.; Morin, G.; Tai, I.T. The interaction between SPARC and GRP78 interferes with ER stress signaling and potentiates apoptosis via PERK/eIF2α and IRE1α/XBP-1 in colorectal cancer. Cell Death Dis., 2019, 10(7), 504.
[http://dx.doi.org/10.1038/s41419-019-1687-x] [PMID: 31243264]
[67]
Axten, J.M.; Medina, J.R.; Feng, Y.; Shu, A.; Romeril, S.P.; Grant, S.W.; Li, W.H.; Heerding, D.A.; Minthorn, E.; Mencken, T.; Atkins, C.; Liu, Q.; Rabindran, S.; Kumar, R.; Hong, X.; Goetz, A.; Stanley, T.; Taylor, J.D.; Sigethy, S.D.; Tomberlin, G.H.; Hassell, A.M.; Kahler, K.M.; Shewchuk, L.M.; Gampe, R.T. Discovery of 7-methyl-5-(1-[3-(trifluoromethyl)phenyl]acetyl-2,3-dihydro-1H-indol-5-yl)-7H-p yrrolo[2,3-d]pyrimidin-4-amine (GSK2606414), a potent and selective first-in-class inhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK). J. Med. Chem., 2012, 55(16), 7193-7207.
[http://dx.doi.org/10.1021/jm300713s] [PMID: 22827572]
[68]
Moreno, J.A.; Halliday, M.; Molloy, C.; Radford, H.; Verity, N.; Axten, J.M.; Ortori, C.A.; Willis, A.E.; Fischer, P.M.; Barrett, D.A.; Mallucci, G.R. Oral treatment targeting the unfolded protein response prevents neurodegeneration and clinical disease in prion-infected mice. Sci. Transl. Med., 2013, 5(206), 206ra138
[http://dx.doi.org/10.1126/scitranslmed.3006767] [PMID: 24107777]
[69]
Mercado, G.; Castillo, V.; Soto, P.; López, N.; Axten, J.M.; Sardi, S.P.; Hoozemans, J.J.M.; Hetz, C. Targeting PERK signaling with the small molecule GSK2606414 prevents neurodegeneration in a model of Parkinson’s disease. Neurobiol. Dis., 2018, 112, 136-148.
[http://dx.doi.org/10.1016/j.nbd.2018.01.004] [PMID: 29355603]
[70]
Atkins, C.; Liu, Q.; Minthorn, E.; Zhang, S.Y.; Figueroa, D.J.; Moss, K.; Stanley, T.B.; Sanders, B.; Goetz, A.; Gaul, N.; Choudhry, A.E.; Alsaid, H.; Jucker, B.M.; Axten, J.M.; Kumar, R. Characterization of a novel PERK kinase inhibitor with antitumor and antiangiogenic activity. Cancer Res., 2013, 73(6), 1993-2002.
[http://dx.doi.org/10.1158/0008-5472.CAN-12-3109] [PMID: 23333938]
[71]
Rojas-Rivera, D.; Delvaeye, T.; Roelandt, R.; Nerinckx, W.; Augustyns, K.; Vandenabeele, P.; Bertrand, M.J.M. When PERK inhibitors turn out to be new potent RIPK1 inhibitors: Critical issues on the specificity and use of GSK2606414 and GSK2656157. Cell Death Differ., 2017, 24(6), 1100-1110.
[http://dx.doi.org/10.1038/cdd.2017.58] [PMID: 28452996]
[72]
Hanaoka, M.; Ishikawa, T.; Ishiguro, M.; Tokura, M.; Yamauchi, S.; Kikuchi, A.; Uetake, H.; Yasuno, M.; Kawano, T. Expression of ATF6 as a marker of pre-cancerous atypical change in ulcerative colitis-associated colorectal cancer: A potential role in the management of dysplasia. J. Gastroenterol., 2018, 53(5), 631-641.
[http://dx.doi.org/10.1007/s00535-017-1387-1] [PMID: 28884228]
[73]
Liu, C.Y.; Hsu, C.C.; Huang, T.T.; Lee, C.H.; Chen, J.L.; Yang, S.H.; Jiang, J.K.; Chen, W.S.; Lee, K.D.; Teng, H.W. ER stress-related ATF6 upregulates CIP2A and contributes to poor prognosis of colon cancer. Mol. Oncol., 2018, 12(10), 1706-1717.
[http://dx.doi.org/10.1002/1878-0261.12365] [PMID: 30063110]
[74]
Jin, C.; Jin, Z.; Chen, N.Z.; Lu, M.; Liu, C.B.; Hu, W.L.; Zheng, C.G. Activation of IRE1α-XBP1 pathway induces cell proliferation and invasion in colorectal carcinoma. Biochem. Biophys. Res. Commun., 2016, 470(1), 75-81.
[http://dx.doi.org/10.1016/j.bbrc.2015.12.119] [PMID: 26742428]
[75]
Ji, H.; Huang, C.; Wu, S.; Kasim, V. XBP1-s promotes colorectal cancer cell proliferation by inhibiting TAp73 transcriptional activity. Biochem. Biophys. Res. Commun., 2019, 508(1), 203-209.
[http://dx.doi.org/10.1016/j.bbrc.2018.11.112] [PMID: 30473215]
[76]
Mhaidat, N.M.; Alzoubi, K.H.; Abushbak, A. X-box binding protein 1 (XBP-1) enhances colorectal cancer cell invasion. J. Chemother., 2015, 27(3), 167-173.
[http://dx.doi.org/10.1179/1973947815Y.0000000006] [PMID: 25692573]
[77]
Spaan, C.N.; Smit, W.L.; van Lidth de Jeude, J.F.; Meijer, B.J.; Muncan, V.; van den Brink, G.R.; Heijmans, J. Expression of UPR effector proteins ATF6 and XBP1 reduce colorectal cancer cell proliferation and stemness by activating PERK signaling. Cell Death Dis., 2019, 10(7), 490.
[http://dx.doi.org/10.1038/s41419-019-1729-4] [PMID: 31227689]
[78]
Haze, K.; Yoshida, H.; Yanagi, H.; Yura, T.; Mori, K. Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. Mol. Biol. Cell, 1999, 10(11), 3787-3799.
[http://dx.doi.org/10.1091/mbc.10.11.3787] [PMID: 10564271]
[79]
Vandewynckel, Y.P.; Laukens, D.; Geerts, A.; Bogaerts, E.; Paridaens, A.; Verhelst, X.; Janssens, S.; Heindryckx, F.; Van Vlierberghe, H. The paradox of the unfolded protein response in cancer. Anticancer Res., 2013, 33(11), 4683-4694.
[PMID: 24222102]
[80]
Chang, M.Y.; Shen, Y.L. Linalool exhibits cytotoxic effects by activating antitumor immunity. Molecules, 2014, 19(5), 6694-6706.
[http://dx.doi.org/10.3390/molecules19056694] [PMID: 24858101]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 20
ISSUE: 3
Year: 2020
Page: [223 - 238]
Pages: 16
DOI: 10.2174/1568009620666200106114826
Price: $65

Article Metrics

PDF: 35
HTML: 4
EPUB: 1
PRC: 1