Src Kinase and Mitogen-Activated Protein Kinases in the Progression from Normal to Malignant Endometrium

Abstract

Purpose: The purpose of this research was to determine whether a correlation exists between the levels of activated mitogen-activated protein kinase (MAPK) and Src kinases and the progression from normal to malignant endometrium.Experimental Design: We measured total and phosphorylated levels for extracellular signal-regulated kinase 1/2, p38, stress-activated protein kinase/c-Jun NH 2 -terminal kinase, and Src kinases from 33 frozen endometrial adenocarcinomas and 38 benign endometrial specimens by quantitation of signals from Western blots using antibodies against these kinases.Results: Elevated phospho-extracellular signal-regulated kinase 1/2 (150 ؎ 40 versus 46 ؎ 7; P ‫؍‬ 0.03), phosphoSrc (28 ؎ 5 versus 4 ؎ 1), and phospho-p38 (131 ؎ 16 versus 27 ؎ 7; P < 0.001) was detected in benign versus malignant endometrium when the Western blot signal of activated kinase was normalized to total kinase levels and ␤ actin. A modest increase in active c-Jun NH 2 -terminal kinase was detected in carcinoma versus benign specimens (51 ؎ 13 versus 43 ؎ 10; P ‫؍‬ 0.8). Expression of total kinases (normalized to ␤-actin) was higher in carcinoma versus benign specimens, respectively (extracellular signal-regulated kinase 1/2, 9 ؎ 2 versus 0.7 ؎ 0.1; Src, 7 ؎ 2 versus 0.4 ؎ 0.1; stress-activated protein kinase c-Jun NH 2 -terminal kinase, 2 ؎ 0.4 versus 0.2 ؎ 0.02; P < 0.001; and p38, 1 ؎ 0.2 versus 0.4 ؎ 0.1; P < 0.01). Immunohistochemistry for active and total Src kinases and MAPKs detected positive staining in epithelial and stroma cells.Conclusions: These data demonstrated that, in contrast with breast cancer, the progression from normal to malignant endometrium is not associated with activation of MAPK and Src kinases. Elevation of these active kinases in benign endometrium may contribute to endometrial resistance to the antiestrogen action of tamoxifen.

c-Jun N-terminal kinase regulates apoptosis in endometrial cancer cells

“…Consistent with our results, active, phospho-JNK levels coincided with a decrease in estrogen and progesterone levels, which induced apoptosis in cultured endometrial cells [42,43]. Endometrial adenocarcinomas exhibited increased JNK expression relative to benign endometrium but no significant increase in JNK phosphorylation/activation was detected in tumors of increasing grade [12], suggesting that JNK does not exhibit oncogenic activity associated with progression to malignancy. However, JNK may also function as a tumor suppressor, regulating apoptosis and response to chemotherapy [7,8,11] and, prior to this study, the role of JNK in apoptotic responses in endometrial cancer cells had not been addressed.…”

“…However, since our data show that JNK can be activated independently of PKCd and higher-grade tumors retain JNK expression and activity [12], JNK activation, by PKCd-independent pathways, may mediate apoptotic responses to DNA damage in endometrial adenocarcinoma, despite a reduction in PKCd expression.…”

“…Expression of JNK is elevated in endometrial carcinomas relative to benign endometrium [12], but its role as a promoter or suppressor of tumorigenesis is not understood. Apoptosis is a critical component of normal endometrial physiology and its aberrant regulation is a hallmark of progression to malignancy [13][14][15].…”

Leptin utilizes Jun N-terminal kinases to stimulate the invasion of MCF-7 breast cancer cells

“…3a). Elevated levels of phosphorylated JNK have been found in breast tumors [41]. JNK activation has been shown to mediate the invasive activity of breast cancer cells [42][43][44].…”

KX-01, a novel Src kinase inhibitor directed toward the peptide substrate site, synergizes with tamoxifen in estrogen receptor α positive breast cancer

“…Previous studies from this laboratory demonstrated that active kinases are elevated in benign when compared to cancerous endometrium raising the possibility that elevation of active kinases in benign endometrium could contribute to the endometrial oncogenic transformation [10]. Additional work demonstrated that c-Src promoted tamoxifen agonist activity in Ishikawa endometrial cells [11].…”