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S.A. Mantey

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    MINI 21 - Novel Targets (ID 133)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      MINI21.08 - Bombesin Receptor Subtype-3: An Underappreciated Growth Factor in Lung Cancer (ID 722)

      16:45 - 18:15  |  Author(s): S.A. Mantey

      • Abstract
      • Presentation
      • Slides

      Human bombesin receptors (BnR) are one of the most frequently over-expressed receptor families by human lung-cancers. It is known the activation of the classical members of the BnR family (GRPR, NMBR), causes a marked effect on cell-signaling and growth, often autocrine in nature, on lung-cancer cells. In addition, it has been discovered that the orphan receptor related to the BnR family, BRS-3, is widely distributed in central/peripheral normal tissues, and numerous tumors include lung-cancer cells. However, in contrast to the classical BnRs (GRPR, NMBR), BRS-3 has received little attention in lung-cancer in large part due to the fact its natural ligand is still unknown, and also because, until recently, the lack of specific pharmacological tools to study it. To address this, in this study, we examined the frequency of hBRS-3 expression in lung-cancer cells, and the effects of specific hBRS-3 activation on cell-signaling and cell-function (growth) in different lung-cancer cell lines.

      17 human lung-cancer (LC) cell lines were studied (9 NSCLC, 8 SCLC), as well as hBRS3 transfected H1299 and Balb 3T3 cells. The BRS-3 selective agonist, MK-5046 and selective BRS-3 antagonist, Bantag-1 were used. BnR expression was assessed by PCR using specific primers for hBRS3, hGRPR or hNMBR. Receptor activation was determined by assessing PLC and MAPK cascade activation using Western Blotting, and cytosolic Ca[2+] release. Proliferation was studied by clonogenic and [[3]H]-Thymidine assays, and EGFR transactivation was assessed using Western blotting.

      Of the 17 LC cell lines, 9 (53%) express hBRS3 [H358, H460, H520, H720, H727, H69, H82, N417, H510], 14 (82%) express hGRPR [H28, H157, H358, H520, A549, H838, H1299, SK-LU-1, H720, H727, H69, H82, H345, H510] and 13 (77%) express hNMBR [H28, H157, H358, A549, H838, H1299, SK-LU-1, H720, H727, H82, H345, N417, H510]. MK-5046 stimulated PLC activation in 6/9 cells which express hBRS3 (H358, H720, H727, H69, H82, N417), and MAPK activation in all 9 hBRS3 cell lines. Cytosolic Ca[2+] increased with MK-5046 addition in all hBRS-3-containing cells, included Balb and H1299 transfected cells, except in H358 cells. Similarly, MK-5046 increased [3]H-Thymidine uptake in 5/9 cells (H460, H520, H720, H727, H82, H510), as well as in Balb and H1299 hBRS-3 transfected cells, and this increase was in a dose-response manner in H727, H69 and N417 cells. MK-5046 stimulated the clonal growth of N417 and H727 cells. MK-5046 addition to H358, H460, H727 (NSCLC) and H69, N417, H510 (SCLC) caused Tyr[1068] phosphorylation of the EGFR.

      These results show the orphan human BnR, hBRS-3 is present in more than one-half of human lung cancer cells. Furthermore, these receptors are functional with their activation effecting cell signaling (MAPK, PLC, Ca[2+]) and cell growth. Transactivation of EGFR is likely an important transduction cascade. These results suggest this orphan BnR, similar to classical BNRs, will be important to assess for growth effects and expression in human lung tumors, and its pharmacological inhibition may be a useful therapeutic approach.

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