Selective p38 Activation in Human Non–Small Cell Lung Cancer

Abstract

The mitogen-activated protein kinase (MAPK) pathways transmit signals from the cell membrane to the nucleus. Activation of MAPK cascades may play a role in malignant transformation. We hypothesized that enhanced expression of one or more of these pathways would occur in human lung cancers. Using Western blot analysis of tissue homogenates from resected non- small cell lung cancers and matched non-neoplastic lung tissue, we determined that only activated p38 was consistently increased in tumor compared with normal tissue. In vitro kinase assays confirmed that the levels of activated MAPK correlated with the activity of the enzymes, and immunohistochemical analysis confirmed the cellular localization of the activated MAPKs. We incubated a lung cancer cell line in a hypoxic chamber to simulate the hypoxic environment in solid lung tumors, but found no increase in p38 activation. Contrary to our expectations, ERK and JNK, the MAPK pathways traditionally associated with cell growth and perhaps malignant transformation, were not consistently activated in the human lung tumor samples. However, p38, a MAPK usually associated with stress responses, growth arrest, and apoptosis, was activated in all of the human lung cancer samples, suggesting an additional role for this pathway in malignant cell growth or transformation.

Reovirus oncolysis: The Ras/RalGEF/p38 pathway dictates host cell permissiveness to reovirus infection

“…41). Activation of p38 has also been reported in a number of human cancers, including non-small-cell lung carcinomas and colon polyps, as well as in the progression from follicular to diffuse large B cell lymphoma (42)(43)(44). In light of our findings, the fact that these signaling pathways are commonly activated in cancer is promising for reovirus use as a cancer therapy.…”

Proline isomerisation as a novel regulatory mechanism for p38MAPK activation and functions

“…41,42 Although the direct correlation between expression of cyclophilins and phosphorylation of p38MAPK has not been established, increased levels of phosphorylated p38MAPK have been described in various cancers. 8,9,[12][13][14]35,43 In this study, we found that cyclophilinmediated isomerisation could be a critical step in the activation of p38MAPK, which could explain the correlative evidence in the literature concerning the overexpression of cyclophilins and an increase in p38MAPK phosphorylation. This in turn could suggest that different cyclophilins and in particular CypA can function as a molecular switch to modulate p38MAPK signalling to adjust to environmental changes, thus modulating cancer cell survival.…”

“…9,10 Similarly, overexpression or activation of p38MAPK has been reported in lymphomas, thyroid neoplasms and human lung tumours. [11][12][13] In addition, inhibition of p38MAPK activity enhances apoptosis and cell sensitivity during administration of chemotherapy drugs. [14][15][16][17] The key regulatory sequence within p38MAPK is Thr180-Gly181-Tyr182, in which Thr and Tyr residues are phosphorylated to increase p38MAPK activity by allowing easier access to its active site.…”

Characterization of LY2228820 Dimesylate, a Potent and Selective Inhibitor of p38 MAPK with Antitumor Activity

“…Higher serum and alveolar lavage IL-6 and CXCL8 levels are associated with survival of patient with shorter lung cancer (40). In addition, p38a MAPK is highly activated in NSCLC relative to normal lung tissue (41). CXCL8 is also higher in the serum and cystic fluid from patients with ovarian cancer as compared with healthy patients or those with benign cysts (14) and increased CXCL8 expression correlated with more advanced stages of disease.…”