towards improved death receptor targeted therapy for ... - TI Pharma
towards improved death receptor targeted therapy for ... - TI Pharma towards improved death receptor targeted therapy for ... - TI Pharma
p38 and JNK induction by TRAIL indirect way. The precise mechanism by which RIP1 prevents activation of JNK and is involved in the proapoptotic activation of p38 remains elusive. Figure 7. Proposed model for TRAIL‐induced p38 and JNK activation leading to pro‐apoptotic and pro‐survival effects. TRAIL activates the pro‐apoptotic activity of p38 in a RIP1‐dependent way. JNK activation occurs following cleavage of RIP1 by caspase‐8 and JNK on its turn has a suppressive effect on RIP1 cleavage via as yet unknown mechanisms. P38 and JNK affect apoptosis by modulating the expression of their know substrate Mcl‐1, with p38 and JNK leading to down‐ or upregulation of Mcl‐ 1 levels, respectively. As JNK was found to have a pro‐survival effect in TRAIL signaling in NSCLC, it would be interesting to combine TRAIL with JNK inhibitors in this cancer type. Currently, some JNK inhibitors such as the isoquinolones and piperazine amides are in development and combination therapies with TRAIL await further testing [43]. It should be noted that the short JNK1 isoforms were found to be anti‐apoptotic, while the long isoforms transmitted a pro‐apoptotic signal in response to TRAIL in colon cancer cells [44]. So, the design of JNK isoform selective inhibitors isoform inhibitors should also be taken into consideration. Here, we did not distinguish between the different isoforms of JNK, as SP600125 inhibits the JNK1,‐2, and ‐3 isoforms with similar potency [24]. In conclusion, we found that TRAIL induced the activation of the MAP kinases JNK and p38 in NSCLC cells in which RIP1 played a modulatory role, and cumulating in changes in Mcl‐1 expression and subsequent apoptosis activation. In a subset of NSCLC tumors inhibition of JNK may provide a strategy for enhancing TRAIL‐induced apoptosis. Acknowledgements This research was performed within the framework of project T3‐112 of the Dutch Top Institute Pharma and supported by grant RUG2011‐5211 from the Dutch Cancer Society. Conflict of interest None ‐ 55 ‐
Chapter 3 Reference List 1. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin 2010; 60(5):277‐ 300. 2. Blackstock AW, Govindan R. Definitive chemoradiation for the treatment of locally advanced non small‐cell lung cancer. J Clin Oncol 2007; 25(26):4146‐4152. 3. Lu C, Lee JJ, Komaki R, Herbst RS, Feng L, Evans WK et al. Chemoradiotherapy with or without AE‐941 in stage III non‐small cell lung cancer: a randomized phase III trial. J Natl Cancer Inst 2010; 102(12):859‐865. 4. Falschlehner C, Emmerich CH, Gerlach B, Walczak H. TRAIL signalling: decisions between life and death. Int J Biochem Cell Biol 2007; 39(7‐8):1462‐1475. 5. Gonzalvez F, Ashkenazi A. New insights into apoptosis signaling by Apo2L/TRAIL. Oncogene 2010; 29(34):4752‐4765. 6. Johnstone RW, Frew AJ, Smyth MJ. The TRAIL apoptotic pathway in cancer onset, progression and therapy. Nat Rev Cancer 2008; 8(10):782‐798. 7. Hoogwater FJ, Nijkamp MW, Smakman N, Steller EJ, Emmink BL, Westendorp BF et al. Oncogenic K‐Ras turns death receptors into metastasis‐promoting receptors in human and mouse colorectal cancer cells. Gastroenterology 2010; 138(7):2357‐2367. 8. Ishimura N, Isomoto H, Bronk SF, Gores GJ. Trail induces cell migration and invasion in apoptosis‐resistant cholangiocarcinoma cells. Am J Physiol Gastrointest Liver Physiol 2006; 290(1):G129‐G136. 9. Azijli K, Yuvaraj S, Peppelenbosch MP, Wurdinger T, Dekker H, Joore J et al. Kinome profiling of non‐canonical TRAIL signaling reveals RIP1‐Src‐STAT3 dependent invasion in resistant non‐small cell lung cancer cells. J Cell Sci 2012. 10. Karacay B, Sanlioglu S, Griffith TS, Sandler A, Bonthius DJ. Inhibition of the NF‐kappaB pathway enhances TRAIL‐mediated apoptosis in neuroblastoma cells. Cancer Gene Ther 2004; 11(10):681‐690. 11. Kim YS, Schwabe RF, Qian T, Lemasters JJ, Brenner DA. TRAIL‐mediated apoptosis requires NF‐kappaB inhibition and the mitochondrial permeability transition in human hepatoma cells. Hepatology 2002; 36(6):1498‐1508. 12. Secchiero P, Gonelli A, Carnevale E, Milani D, Pandolfi A, Zella D et al. TRAIL promotes the survival and proliferation of primary human vascular endothelial cells by activating the Akt and ERK pathways. Circulation 2003; 107(17):2250‐2256. 13. Thiefes A, Wolter S, Mushinski JF, Hoffmann E, ttrich‐Breiholz O, Graue N et al. Simultaneous blockade of NFkappaB, JNK, and p38 MAPK by a kinase‐inactive mutant of the protein kinase TAK1 sensitizes cells to apoptosis and affects a distinct spectrum of tumor necrosis factor [corrected] target genes. J Biol Chem 2005; 280(30):27728‐27741. 14. Vaculova A, Hofmanova J, Soucek K, Kozubik A. Different modulation of TRAIL‐induced apoptosis by inhibition of pro‐survival pathways in TRAIL‐sensitive and TRAIL‐resistant colon cancer cells. FEBS Lett 2006; 580(28‐29):6565‐6569. 15. Weldon CB, Parker AP, Patten D, Elliott S, Tang Y, Frigo DE et al. Sensitization of apoptotically‐resistant breast carcinoma cells to TNF and TRAIL by inhibition of p38 mitogen‐activated protein kinase signaling. Int J Oncol 2004; 24(6):1473‐1480. 16. Zhang XD, Borrow JM, Zhang XY, Nguyen T, Hersey P. Activation of ERK1/2 protects melanoma cells from TRAIL‐induced apoptosis by inhibiting Smac/DIABLO release from mitochondria. Oncogene 2003; 22(19):2869‐2881. 17. Mathews ST, Plaisance EP, Kim T. Imaging systems for westerns: chemiluminescence vs. infrared detection. Methods Mol Biol 2009; 536:499‐513. 18. Brummelkamp TR, Bernards R, Agami R. Stable suppression of tumorigenicity by virus‐ mediated RNA interference. Cancer Cell 2002; 2(3):243‐247. 19. van Leuken R, Clijsters L, van ZW, Lim D, Yao X, Wolthuis RM et al. Polo‐like kinase‐1 controls Aurora A destruction by activating APC/C‐Cdh1. PLoS One 2009; 4(4):e5282. ‐ 56 ‐
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p38 and JNK induction by TRAIL<br />
indirect way. The precise mechanism by which RIP1 prevents activation of JNK and is<br />
involved in the proapoptotic activation of p38 remains elusive.<br />
Figure 7. Proposed model <strong>for</strong> TRAIL‐induced p38 and JNK activation leading to pro‐apoptotic and<br />
pro‐survival effects. TRAIL activates the pro‐apoptotic activity of p38 in a RIP1‐dependent way. JNK<br />
activation occurs following cleavage<br />
of RIP1 by caspase‐8 and JNK on its turn has a suppressive effect<br />
on RIP1 cleavage via as yet unknown mechanisms. P38 and JNK affect apoptosis by modulating the<br />
expression of their know substrate Mcl‐1, with p38 and JNK leading to down‐ or upregulation of Mcl‐<br />
1 levels, respectively.<br />
As JNK was found to have a pro‐survival effect in TRAIL signaling in NSCLC, it would be<br />
interesting to combine TRAIL with JNK inhibitors in this cancer type. Currently, some JNK<br />
inhibitors such as the isoquinolones and piperazine amides are in development and<br />
combination therapies with TRAIL await further testing [43]. It should be noted that the<br />
short JNK1 iso<strong>for</strong>ms were found to be anti‐apoptotic, while the long iso<strong>for</strong>ms transmitted<br />
a pro‐apoptotic signal in response to TRAIL in colon cancer cells [44]. So, the design of JNK<br />
iso<strong>for</strong>m selective inhibitors iso<strong>for</strong>m inhibitors should also be taken into consideration.<br />
Here, we did not distinguish between the different iso<strong>for</strong>ms of JNK, as SP600125 inhibits<br />
the JNK1,‐2, and ‐3 iso<strong>for</strong>ms with similar potency [24].<br />
In conclusion, we found that TRAIL induced the activation of the MAP kinases JNK and p38<br />
in NSCLC cells in which RIP1 played a modulatory role, and cumulating in changes in Mcl‐1<br />
expression and subsequent apoptosis activation. In a subset of NSCLC tumors inhibition of<br />
JNK may provide a strategy <strong>for</strong> enhancing TRAIL‐induced apoptosis.<br />
Acknowledgements<br />
This<br />
research was per<strong>for</strong>med within the framework of project T3‐112 of the Dutch Top<br />
Institute <strong>Pharma</strong> and supported<br />
by grant RUG2011‐5211 from the Dutch Cancer Society.<br />
Conflict of interest<br />
None<br />
‐ 55 ‐
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