Specific role of JNK in the maintenance of the tumor-initiating capacity of A549 human non-small cell lung cancer cells

Okada,Masashi; Shibuya,Keita; Sato,Atsushi; Seino,Shizuka; Watanabe,Eriko; Suzuki,Shuhei; Seino,Manabu; Kitanaka,Chifumi

doi:10.3892/or.2013.2655

Specific role of JNK in the maintenance of the tumor-initiating capacity of A549 human non-small cell lung cancer cells

Authors:
- Masashi Okada
- Keita Shibuya
- Atsushi Sato
- Shizuka Seino
- Eriko Watanabe
- Shuhei Suzuki
- Manabu Seino
- Chifumi Kitanaka
View Affiliations

Affiliations: Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata 990-9585, Japan
Published online on: August 2, 2013 https://doi.org/10.3892/or.2013.2655
Pages: 1957-1964

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Deregulation of c-Jun NH2-terminal kinase (JNK) signaling is now increasingly reported in a variety of human malignancies. Non-small cell lung cancer (NSCLC) is among such human malignancies with aberrant JNK activation; yet the exact role(s) of JNK deregulation in NSCLC biology, in particular in vivo, remains unclear. Here, we demonstrated a specific role of JNK in the control of the tumor-initiating capacity of A549 cells derived from human lung adenocarcinoma, a major subtype of NSCLC. Despite its potent inhibitory activity on A549 cell growth in vitro, SP600125, a reversible JNK inhibitor, failed to inhibit the growth of pre-established A549 xenografts in vivo when systemically administered. Nevertheless, the same SP600125 treatment caused a marked reduction in the tumor-initiating population within the A549 tumors, suggesting that JNK may be specifically required in vivo for the maintenance of the tumor-initiating population of tumor cells rather than for proliferation and survival of the entire cell population. Furthermore, A549 cells either pre-treated with SP600125 or transiently transfected with siRNAs against the JNK genes in vitro showed substantially reduced ability to initiate tumor formation upon implantation into nude mice, implying that the cell intrinsic JNK activity of A549 cells is essential for the maintenance of their tumor-initiating capacity. To our knowledge, this is the first demonstration that JNK is involved in the control of the tumor-initiating capacity of NSCLC cells. Our findings also give rise to an intriguing possibility that therapies targeting JNK could contribute to prevention of relapse and/or metastasis of NSCLC through elimination of tumor-initiating cells.

View Figures

View References

1	Weston CR and Davis RJ: The JNK signal transduction pathway. Curr Opin Cell Biol. 19:142–149. 2007. View Article : Google Scholar : PubMed/NCBI
2	Kennedy NJ and Davis RJ: Role of JNK in tumor development. Cell Cycle. 2:199–201. 2003.PubMed/NCBI
3	Wagner EF and Nebreda AR: Signal integration by JNK and p38 MAPK pathways in cancer development. Nat Rev Cancer. 9:537–549. 2009. View Article : Google Scholar : PubMed/NCBI
4	Chen F: JNK-induced apoptosis, compensatory growth, and cancer stem cells. Cancer Res. 72:379–386. 2012. View Article : Google Scholar : PubMed/NCBI
5	Kitanaka C, Sato A and Okada M: JNK signaling in the control of the tumor-initiating capacity associated with cancer stem cells. Genes Cancer. January 22–2013.(Epub ahead of print). View Article : Google Scholar
6	Matsuda K, Sato A, Okada M, et al: Targeting JNK for therapeutic depletion of stem-like glioblastoma cells. Sci Rep. 2:5162012. View Article : Google Scholar : PubMed/NCBI
7	Yoon CH, Kim MJ, Kim RK, et al: c-Jun N-terminal kinase has a pivotal role in the maintenance of self-renewal and tumorigenicity in glioma stem-like cells. Oncogene. 31:4655–4666. 2012. View Article : Google Scholar : PubMed/NCBI
8	Yu Y, Ramena G and Elble RC: The role of cancer stem cells in relapse of solid tumors. Front Biosci. 4:1528–1541. 2012. View Article : Google Scholar : PubMed/NCBI
9	Malik B and Nie D: Cancer stem cells and resistance to chemo and radio therapy. Front Biosci. 4:2142–2149. 2012. View Article : Google Scholar : PubMed/NCBI
10	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar
11	Collins LG, Haines C, Perkel R and Enck RE: Lung cancer: diagnosis and management. Am Fam Physician. 75:56–63. 2007.
12	Li JY, Wang H, May S, et al: Constitutive activation of c-Jun N-terminal kinase correlates with histologic grade and EGFR expression in diffuse gliomas. J Neurooncol. 88:11–17. 2008. View Article : Google Scholar : PubMed/NCBI
13	Antonyak MA, Kenyon LC, Godwin AK, et al: Elevated JNK activation contributes to the pathogenesis of human brain tumors. Oncogene. 21:5038–5046. 2002. View Article : Google Scholar : PubMed/NCBI
14	Tsuiki H, Tnani M, Okamoto I, et al: Constitutively active forms of c-Jun NH₂-terminal kinase are expressed in primary glial tumors. Cancer Res. 63:250–255. 2003.PubMed/NCBI
15	Cui J, Han SY, Wang C, et al: c-Jun NH₂-terminal kinase 2α2 promotes the tumorigenicity of human glioblastoma cells. Cancer Res. 66:10024–10031. 2006.
16	Khatlani TS, Wislez M, Sun M, et al: c-Jun N-terminal kinase is activated in non-small-cell lung cancer and promotes neoplastic transformation in human bronchial epithelial cells. Oncogene. 26:2658–2666. 2007. View Article : Google Scholar : PubMed/NCBI
17	Nitta RT, Del Vecchio CA, Chu AH, Mitra SS, Godwin AK and Wong AJ: The role of the c-Jun N-terminal kinase 2-α-isoform in non-small cell lung carcinoma tumorigenesis. Oncogene. 30:234–244. 2011.
18	Lee JJ, Lee JH, Ko YG, Hong SI and Lee JS: Prevention of premature senescence requires JNK regulation of Bcl-2 and reactive oxygen species. Oncogene. 29:561–575. 2010. View Article : Google Scholar : PubMed/NCBI
19	Perez EA, Hack FM, Fletcher TS and Chou TC: Modulation of intrinsic in vitro resistance to carboplatin by edatrexate in the A549 human nonsmall cell lung cancer cell line. Oncol Res. 6:151–156. 1994.PubMed/NCBI
20	Eramo A, Ricci-Vitiani L, Zeuner A, et al: Chemotherapy resistance of glioblastoma stem cells. Cell Death Differ. 13:1238–1241. 2006. View Article : Google Scholar : PubMed/NCBI
21	Eramo A, Lotti F, Sette G, et al: Identification and expansion of the tumorigenic lung cancer stem cell population. Cell Death Differ. 15:504–514. 2008. View Article : Google Scholar : PubMed/NCBI
22	Ricci-Vitiani L, Lombardi DG, Pilozzi E, et al: Identification and expansion of human colon cancer-initiating cells. Nature. 445:111–115. 2007. View Article : Google Scholar : PubMed/NCBI
23	Sato A, Sunayama J, Okada M, et al: Glioma-initiating cell elimination by metformin activation of FOXO3 via AMPK. Stem Cells Transl Med. 1:811–824. 2012. View Article : Google Scholar : PubMed/NCBI
24	Bennett BL, Sasaki DT, Murray BW, et al: SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase. Proc Natl Acad Sci USA. 98:13681–13686. 2001. View Article : Google Scholar : PubMed/NCBI
25	Xia Z, Dickens M, Raingeaud J, Davis RJ and Greenberg ME: Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science. 270:1326–1331. 1995. View Article : Google Scholar : PubMed/NCBI
26	Dhanasekaran DN and Reddy EP: JNK signaling in apoptosis. Oncogene. 27:6245–6251. 2008. View Article : Google Scholar : PubMed/NCBI
27	Verheij M, Ruiter GA, Zerp SF, et al: The role of the stress-activated protein kinase (SAPK/JNK) signaling pathway in radiation-induced apoptosis. Radiother Oncol. 47:225–232. 1998. View Article : Google Scholar : PubMed/NCBI
28	Fan M and Chambers TC: Role of mitogen-activated protein kinases in the response of tumor cells to chemotherapy. Drug Resist Updat. 4:253–267. 2001. View Article : Google Scholar : PubMed/NCBI
29	Cellurale C, Sabio G, Kennedy NJ, et al: Requirement of c-Jun NH₂-terminal kinase for Ras-initiated tumor formation. Mol Cell Biol. 31:1565–1576. 2011.PubMed/NCBI
30	Jackson EL, Willis N, Mercer K, et al: Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras. Genes Dev. 15:3243–3248. 2001. View Article : Google Scholar : PubMed/NCBI
31	Vachtenheim J: Occurrence of ras mutations in human lung cancer. Minireview Neoplasma. 44:145–149. 1997.PubMed/NCBI
32	Kadara H, Kabbout M and Wistuba II: Pulmonary adenocarcinoma: a renewed entity in 2011. Respirology. 17:50–65. 2012. View Article : Google Scholar : PubMed/NCBI
33	Kurtze I, Sonnemann J and Beck JF: KRAS-mutated non-small cell lung cancer cells are responsive to either co-treatment with erlotinib or gefitinib and histone deacetylase inhibitors or single treatment with lapatinib. Oncol Rep. 25:1021–1029. 2011.PubMed/NCBI
34	Okudela K, Hayashi H, Ito T, et al: K-ras gene mutation enhances motility of immortalized airway cells and lung adenocarcinoma cells via Akt activation: possible contribution to non-invasive expansion of lung adenocarcinoma. Am J Pathol. 164:91–100. 2004. View Article : Google Scholar