Abstract B104: Tid1 as a novel target for HSP-directed therapy in NSCLC.

Abstract

Abstract Molecular chaperones, commonly known as heat shock proteins (HSPs), are essential for mammalian cells to maintain homeostasis. HSPs may interact with diverse co-chaperones and induce an ATPase-coupled structural change in client proteins and regulate critical signaling networks. More than 200 client proteins have been identified which may serve as important therapeutic targets in human diseases. The human tumorous imaginal disc 1 (Tid1) protein, a member of the DnaJ domain protein family, is a tumor suppressor and is known to promote ubiquitin-mediated degradation of oncogenic kinases. The Tid1 is a heat shock protein and function as molecular chaperone. In this work, we investigated the role of Tid1 in the tumorigenesis of non-small-cell lung cancer (NSCLC). The expression of two alternatively spliced isoforms of Tid1 (Tid1L and Tid1S) as well as EGFR was examined with RT-PCR and immunohistochemistry (IHC) in tumors from NSCLC patients. The expression of Tid1 was reduced in the majority of NSCLCs and an inverse correlation was observed for the expression of Tid1 and EGFR. Furthermore, we demonstrated that Tid1L, EGFR, HSP70, and HSP90 interacted with each other, and this interaction is dependent on functional DnaJ domain of the Tid1L. Overexpression of the Tid1L in lung cancer cells in vitro inhibited cell proliferation, anchorage-independent growth, and induced apoptosis. We further showed that overexpression of the Tid1L in lung cancer cells attenuated EGFR signaling activity and inhibited the activation of AKT, ERK and STAT3. In contrast, knockdown of Tid1 in EGFR-transfected lung cancer cells markedly increased the stability of EGFR. Taken together, our results support that Tid1L may play a critical role in regulating EGFR signaling in NSCLC; raising the possibility that Tid1 may be a novel target for HSP directed therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B104.