The use of protein array to identify targetable receptor tyrosine kinases for treatment of human colon cancer

Abstract

Abstract. Several studies have reported that activated receptor tyrosine kinases (RTKs) are highly expressed in colon cancer and may promote tumor growth and survival. However, there is little information available as to the function and signaling of RTKs in colon cancers. In the present study, we performed protein array technology to determine the expression status of various RTKs that are activated in colon cancer compared to normal colonic cells and tissues. Of the 42 different phospho-RTKs, 5 (ErbB2, FGFR1, FGFR2a, FGFR3 and MSPR) were activated in Caco-2, SW480, WiDr, Lovo colon cancer cell lines and cancerous tissues. In order to determine the effect of inhibition of RTKs, especially ErbB2, athymic nude mice bearing xenograft tumors were treated with the ErbB2-targeting drug trastuzumab alone, or in combination with 5-Fluorouracil (5-FU). Similar to the treatment of 5-FU alone, trastuzumab suppressed the growth of colon cancer. Combination therapy of trastuzumab and 5-FU inhibited tumor growth significantly compared to the treatment of 5-FU alone or trastuzumab alone. In addition, xenograft tumors were also analyzed by phospho-MAPK protein array. The activity of Akt3/PKBÁ was inhibited with 5-FU alone and trastuzumab, indicating that trastuzumab may inhibit colon cancer growth through ErbB2-Akt3/PKBÁ signaling. These data demonstrate that ErbB2 could be an important candidate for colon cancer therapy and the addition of trastuzumab to 5-FU therapy might augment the clinical response in colon cancer patients. Therefore, the analysis of phospho-RTK expression by protein array as a useful tool might identify novel therapies for individual patients with colon cancer.

Testicular orphan receptor 4 promotes tumor progression and implies poor survival through AKT3 regulation in seminoma

“…A growing number of publications have been highlighting the importance of AKT3 expression in various cancers . Several studies have documented that elevated AKT3 was involved in the regulation of proliferation and invasion in thyroid cancer, malignant melanoma cells and hepatocellular carcinoma . As an oncogene, the activation of Akt3 contributes significantly to increased invasion abilities through upregulation of MYC proto‐oncogene (C‐myc) and vascular endothelial growth factor precursor (VEGF), which are known to trigger tumorigenesis and angiogenesis, respectively.…”

Activation of Akt by the Mammalian Target of Rapamycin Complex 2 Renders Colon Cancer Cells Sensitive to Apoptosis Induced by Nitric Oxide and Akt Inhibitor

“…Although the molecular mechanism by which GTN unlocks colorectal cancer cell resistance is not deciphered, NO may exert its pro-apoptotic effect by altering the Akt inhibitors-mediated activation of RTKs as described by Chandarlapaty et al [29]. It is noteworthy that three RTKs, epidermal growth factor 3 (EGFR-3) or HER3, insulin growth receptor 1 (IGF-1R) and macrophage-stimulating protein receptor (MSPR) are activated in colon cancer cells including SW480 [30,31]. As NO is able to inhibit the function of IGF-1R [32], GTN could render cancer cells sensitive to apoptosis induced by H89 and triciribine.…”

Expression profiles of 507 proteins from a biotin label-based antibody array in human colorectal cancer

“…Previously, we reported activated receptor tyrosine kinase (RTK) arrays in CRC (8). The downregulation of angiogenic factors such as vascular endothelial growth factor (VEGF) and matrix metalloproteinases inhibits invasiveness and tumor development in colon cancer (9).…”