Abstract
Epidermal growth factor receptor (EGFR) is expressed, albeit at low or intermediate levels, in human melanomas at the different stages of tumor progression. Coexpression of EGFR with its ligand TGFα indicates their role in paracrine and autocrine growth regulation of melanomas. As it was previously observed for several types of cancer, specific inhibitors of EGFR-mediated signaling may reduce antiapoptotic properties of cancer cells and sensitize them to cytotoxic drugs. We recently reported that arsenite, particularly in combination with inhibitors of the PI3K-AKT and mitogen-activated protein kinase (MAPK) kinase (MEK)-extracellular signal-regulated kinase (ERK) pathways, induces high levels of apoptosis in different melanomas. Since EGFR signaling operates via activation of the PI3K-AKT and MEK-ERK pathways, we suggested that the combination of arsenite and EGFR inhibitors might also effectively induce apoptosis in melanoma. Here, we demonstrate that a moderate concentration of arsenite (5–10 μ M) indeed upregulates apoptosis induced by EGFR inhibitors in EGFR-positive melanomas. In contrast, induction of apoptosis in melanomas with negligible surface expression of EGFR or with defective EGFR signaling requires direct suppression of the PI3K-AKT and MAPK pathways by specific pharmacological inhibitors in the presence of arsenite. Under these conditions, metastatic melanoma cell lines undergo TNF-related apoptosis-inducing ligand (TRAIL)- and tumor necrosis factor alpha (TNFα)-mediated apoptosis. Taken together, these data provide additional approaches in sensitizing melanomas to the cytotoxic effects of specific inhibitors of survival pathways.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Abbreviations
- Ac-IETD-CHO:
-
N-acetyl-Ile-Glu-Thr-Asp-CHO (aldehyde)
- Ac-LEHD-CHO:
-
N-acetyl-Leu-Glu-His-Asp-CHO (aldehyde)
- AP-1:
-
activator protein-1
- ATF2:
-
activating transcription factor 2
- EGFR:
-
epidermal growth factor receptor
- EMSA:
-
electrophoretic mobility shift assay
- ERK:
-
extracellular signal-regulated kinase
- FACS:
-
fluorescence-activated cell sorter
- HO-1:
-
heme oxygenase-1
- JNK:
-
Jun N-terminal kinase
- IκB:
-
inhibitor of NF-κB
- IKK:
-
inhibitor nuclear factor kappa B kinase
- MAPK:
-
mitogen-activated protein kinase
- MEK:
-
MAPK kinase
- MFI:
-
medium fluorescence intensity
- mTOR:
-
mammalian target of rapamycin
- NF-κB:
-
nuclear factor kappa B
- PARP:
-
poly (ADP-ribose) polymerase
- PI:
-
propidium iodide
- PP IX (Zn2+):
-
Zn-containing protoporphyrin IX
- ROS:
-
reactive oxygen species
- TNFα:
-
tumor necrosis factor alpha
- TNFR:
-
tumor necrosis factor receptor
- TRAIL:
-
TNF-related apoptosis-inducing ligand
References
Alam J and Cook JL . (2003). Curr. Pharm. Des., 9, 2499–2511.
Alam J and Den Z . (1992). J. Biol. Chem., 267, 21894–21900.
Amit S and Ben-Neriah Y . (2003). Semin. Cancer Biol., 13, 15–28.
Berking C, Takemoto R, Schaider H, Showe L, Satyamoorthy K, Robbins P and Herlyn M . (2001). Cancer Res., 61, 8306–8316.
Bjornsti MA and Houghton PJ . (2004). Nat. Rev. Cancer, 4, 335–348.
Blackledge G and Averbuch S . (2004). Br. J. Cancer, 90, 566–572.
Bode AM and Dong Z . (2002). Crit. Rev. Oncol. Hematol., 42, 5–24.
Brouard S, Berberat PO, Tobiasch E, Seldon MP, Bach FH and Soares MP . (2002). J. Biol. Chem., 277, 17950–17961.
Cavigelli M, Li WW, Lin A, Su B, Yoshioka K and Karin M . (1996). EMBO J., 15, 6269–6279.
Chen LF and Greene WC . (2004). Nat. Rev. Mol. Cell. Biol., 5, 392–401.
Chen W, Martindale JL, Holbrook NJ and Liu Y . (1998). Mol. Cell. Biol., 18, 5178–5188.
Chen X, Thakkar H, Tyan F, Gim S, Robinson H, Lee C, Pandey SK, Nwokorie C, Onwudiwe N and Srivastava RK . (2001). Oncogene, 20, 6073–6083.
Cheng HY, Li P, David M, Smithgall TE, Feng L and Lieberman MW . (2004). Oncogene, 23, 3603–3612.
Dancey J and Sausville EA . (2003). Nat. Rev. Drug Discov., 2, 296–313.
Dancey JE . (2004). Cancer Cell, 5, 411–415.
Darnell Jr JE . (2002). Nat. Rev. Cancer, 2, 740–749.
Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR and Futreal PA . (2002). Nature, 417, 949–954.
Dong J, Phelps RG, Qiao R, Yao S, Benard O, Ronai Z and Aaronson SA . (2003). Cancer Res., 63, 3883–3885.
Durante W . (2003). J. Cell. Physiol., 195, 373–382.
Evan GI and Vousden KH . (2001). Nature, 411, 342–348.
Franco AV, Zhang XD, Van Berkel E, Sanders JE, Zhang XY, Thomas WD, Nguyen T and Hersey P . (2001). J. Immunol., 166, 5337–5345.
Giaccone G, Herbst RS, Manegold C, Scagliotti G, Rosell R, Miller V, Natale RB, Schiller JH, Von Pawel J, Pluzanska A, Gatzemeier U, Grous J, Ochs JS, Averbuch SD, Wolf MK, Rennie P, Fandi A and Johnson DH . (2004). J. Clin. Oncol., 22, 777–784.
Gong P, Stewart D, Hu B, Vinson C and Alam J . (2002). Arch. Biochem. Biophys., 405, 265–274.
Griffith TS, Chin WA, Jackson GC, Lynch DH and Kubin MZ . (1998). J. Immunol., 161, 2833–2840.
Gschwind A, Fischer OM and Ullrich A . (2004). Nat. Rev. Cancer, 4, 361–370.
Halaban R . (1996). Semin. Oncol., 23, 673–681.
Hanada M, Feng J and Hemmings BA . (2004). Biochim. Biophys. Acta, 1697, 3–16.
Hayashi T, Hideshima T and Anderson KC . (2003). Br. J. Haematol., 120, 10–17.
Hei TK, Liu SX and Waldren C . (1998). Proc. Natl. Acad. Sci. USA, 95, 8103–8107.
Hershko DD, Robb BW, Hungness ES, Luo G and Hasselgren PO . (2002). J. Cell. Biochem., 84, 687–698.
Huerta-Yepez S, Vega M, Jazirehi A, Garban H, Hongo F, Cheng G and Bonavida B . (2004). Oncogene, 23, 4993–5003.
Ivanov V, Fleming TJ and Malek TR . (1994). J. Immunol., 153, 2394–2406.
Ivanov VN and Hei TK . (2004). J. Biol. Chem., 279, 22747–22758.
Ivanov VN and Ronai Z . (1999). J. Biol. Chem., 274, 14079–14089.
Ivanov VN, Krasilnikov M and Ronai Z . (2002). J. Biol. Chem., 277, 4932–4944.
Jiang BH, Jiang G, Zheng JZ, Lu Z, Hunter T and Vogt PK . (2001). Cell Growth Differ., 12, 363–369.
Johnstone RW, Ruefli AA and Lowe SW . (2002). Cell, 108, 153–164.
Kandel ES and Hay N . (1999). Exp. Cell Res., 253, 210–229.
Kapahi P, Takahashi T, Natoli G, Adams SR, Chen Y, Tsien RY and Karin M . (2000). J. Biol. Chem., 275, 36062–36066.
Karin M, Cao Y, Greten FR and Li ZW . (2002). Nat. Rev. Cancer, 2, 301–310.
Karin M and Lin A . (2002). Nat. Immunol., 3, 221–227.
Karin M, Yamamoto Y and Wang QM . (2004). Nat. Rev. Drug Discov., 3, 17–26.
Kitada S, Pedersen IM, Schimmer AD and Reed JC . (2002). Oncogene, 21, 3459–3474.
Krasilnikov M, Ivanov VN, Dong J and Ronai Z . (2003). Oncogene, 22, 4092–4101.
Lazar-Molnar E, Hegyesi H, Toth S and Falus A . (2000). Cytokine, 12, 547–554.
Lee PJ, Camhi SL, Chin BY, Alam J and Choi AM . (2000). Am. J. Physiol. Lung Cell. Mol. Physiol., 279, L175–82.
Lee PJ, Jiang BH, Chin BY, Iyer NV, Alam J, Semenza GL and Choi AM . (1997). J. Biol. Chem., 272, 5375–5381.
Levitzki A and Gazit A . (1995). Science, 267, 1782–1788.
Levy DE and Darnell Jr JE . (2002). Nat. Rev. Mol. Cell. Biol., 3, 651–662.
Li G, Kalabis J, Xu X, Meier F, Oka M, Bogenrieder T and Herlyn M . (2003). Oncogene, 22, 6891–6899.
Li G, Satyamoorthy K and Herlyn M . (2001). Cancer Res., 61, 3819–3825.
Li M, Cai JF and Chiu JF . (2002). J. Cell. Biochem., 87, 29–38.
Lin A and Karin M . (2003). Semin. Cancer Biol., 13, 107–114.
Liu J, Kadiiska MB, Liu Y, Lu T, Qu W and Waalkes MP . (2001a). Toxicol. Sci., 61, 314–320.
Liu SX, Athar M, Lippai I, Waldren C and Hei TK . (2001b). Proc. Natl. Acad. Sci. USA, 98, 1643–1648.
Ludwig S, Hoffmeyer A, Goebeler M, Kilian K, Hafner H, Neufeld B, Han J and Rapp UR . (1998). J. Biol. Chem., 273, 1917–1922.
Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG, Louis DN, Christiani DC, Settleman J and Haber DA . (2004). N. Engl. J. Med., 350, 2129–2139.
Martin D, Rojo AI, Salinas M, Diaz R, Gallardo G, Alam J, De Galarreta CM and Cuadrado A . (2004). J. Biol. Chem., 279, 8919–8929.
Mathas S, Lietz A, Janz M, Hinz M, Jundt F, Scheidereit C, Bommert K and Dorken B . (2003). Blood, 102, 1028–1034.
Myklebust AT, Helseth A, Breistol K, Hall WA and Fodstad O . (1994). J. Neurooncol., 21, 215–224.
Nicoletti I, Migliorati G, Pagliacci MC, Grignani F and Riccardi C . (1991). J. Immunol. Methods, 139, 271–279.
Orlowski RZ and Baldwin Jr AS . (2002). Trends Mol. Med., 8, 385–389.
Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ, Naoki K, Sasaki H, Fujii Y, Eck MJ, Sellers WR, Johnson BE and Meyerson M . (2004). Science, 304, 1497–1500.
Perlis C and Herlyn M . (2004). Oncologist, 9, 182–187.
Rea MA, Gregg JP, Qin Q, Phillips MA and Rice RH . (2003). Carcinogenesis, 24, 747–756.
Reifenberger J, Knobbe CB, Sterzinger AA, Blaschke B, Schulte KW, Ruzicka T and Reifenberger G . (2004). Int. J. Cancer, 109, 377–384.
Roussel RR and Barchowsky A . (2000). Arch. Biochem. Biophys., 377, 204–212.
Satyamoorthy K, DeJesus E, Linnenbach AJ, Kraj B, Kornreich DL, Rendle S, Elder DE and Herlyn M . (1997). Melanoma Res., 7 (Suppl 2), S35–42.
Satyamoorthy K, Li G, Gerrero MR, Brose MS, Volpe P, Weber BL, Van Belle P, Elder DE and Herlyn M . (2003). Cancer Res., 63, 756–759.
Schlessinger J . (2000). Cell, 103, 211–225.
Shaulian E and Karin M . (2002). Nat. Cell Biol., 4, E131–E136.
Sibilia M, Fleischmann A, Behrens A, Stingl L, Carroll J, Watt FM, Schlessinger J and Wagner EF . (2000). Cell, 102, 211–220.
Snow ET . (1992). Pharmacol. Ther., 53, 31–65.
Threadgill DW, Dlugosz AA, Hansen LA, Tennenbaum T, Lichti U, Yee D, LaMantia C, Mourton T, Herrup K, Harris RC, Barnard JA, Yuspa SH, Coffey RJ and Magnuson T . (1995). Science, 269, 230–234.
Tuveson DA, Weber BL and Herlyn M . (2003). Cancer Cell, 4, 95–98.
von Willebrand M, Zacksenhaus E, Cheng E, Glazer P and Halaban R . (2003). Cancer Res., 63, 1420–1429.
Wakeling AE, Barker AJ, Davies DH, Brown DS, Green LR, Cartlidge SA and Woodburn JR . (1996). Breast Cancer Res. Treat., 38, 67–73.
Yarden Y and Sliwkowski MX . (2001). Nat. Rev. Mol. Cell. Biol., 2, 127–137.
Yih LH, Peck K and Lee TC . (2002). Carcinogenesis, 23, 867–876.
Zhang X, Shan P, Alam J, Davis RJ, Flavell RA and Lee PJ . (2003a). J. Biol. Chem., 278, 22061–22070.
Zhang XD, Borrow JM, Zhang XY, Nguyen T and Hersey P . (2003b). Oncogene, 22, 2869–2881.
Zheng XH, Watts GS, Vaught S and Gandolfi AJ . (2003). Toxicology, 187, 39–48.
Acknowledgements
This work was supported by NIH Grant ES 11804, ES 05786 Superfund Grant P42 ES 10349 and Environmental Center Grant P30 ES 09089. We thank Drs M Herlyn, O Fodstad, R Halaban and Z Ronai for the cell lines; Dr A Chan, Dr S Fuchs, Ms S Baker and Mr JA Gillespie for critical reading of the manuscript.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Ivanov, V., Hei, T. Combined treatment with EGFR inhibitors and arsenite upregulated apoptosis in human EGFR-positive melanomas: a role of suppression of the PI3K-AKT pathway. Oncogene 24, 616–626 (2005). https://doi.org/10.1038/sj.onc.1208125
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1208125
Keywords
This article is cited by
-
Matrine Alleviates Sepsis-Induced Myocardial Injury by Inhibiting Ferroptosis and Apoptosis
Inflammation (2023)
-
2,3,5,6-Tetramethylpyrazine (TMP) down-regulated arsenic-induced heme oxygenase-1 and ARS2 expression by inhibiting Nrf2, NF-κB, AP-1 and MAPK pathways in human proximal tubular cells
Archives of Toxicology (2016)
-
Tetramethylpyrazine (TMP) protects against sodium arsenite-induced nephrotoxicity by suppressing ROS production, mitochondrial dysfunction, pro-inflammatory signaling pathways and programed cell death
Archives of Toxicology (2015)
-
Stability, Complexity and Robustness in Population Dynamics
Acta Biotheoretica (2014)
-
Predictive Power of “A Minima” Models in Biology
Acta Biotheoretica (2012)