CLPTM1L/CRR9 ectodomain interaction with GRP78 at the cell surface signals for survival and chemoresistance upon ER stress in pancreatic adenocarcinoma cells

Abstract

Altered regulation of endoplasmic reticulum (ER) homeostasis has been implicated in many cancers and has recently become a therapeutic and chemosensitization target of interest. We have identified Cleft Lip and Palate Transmembrane 1-Like (CLPTM1L)/Cisplatin Resistance Related Protein 9 (CRR9) as an ER stress related mediator of cytoprotection in pancreatic cancer. We recently demonstrated that CLPTM1L is highly expressed in pancreatic ductal adenocarcinoma and associated with poor outcome. Furthermore, we have discovered that CLPTM1L interacts with phosphoinositol-3-kinase-alpha at the tumor cell surface and causes up-regulation of Bcl-xL and pAkt mediated survival signaling. Here, we demonstrate surface relocalization and survival signaling by CLPTM1L triggered by endoplasmic reticular (ER) stress. We demonstrate the interaction of CLPTM1L with the central ER stress survival mediator, Glucose Regulated Protein 78 (GRP78)/Binding Immunoglobulin Protein (BiP) and PI3K-alpha /p110α. This interaction and surface relocalization of CLPTM1L and GRP78 is induced by ER stress, including that caused by treatment with gemcitabine. We demonstrate that the extracellular loop of CLPTM1L is required for gemcitabine resistance and interaction with GRP78. This interaction and the chemoresistance effect conferred by this pathway is targetable with our recently developed inhibitory CLPTM1L antibodies, which may represent novel modalities of chemosensitization and treatment of pancreatic adenocarcinoma. Anchorage independent growth, GRP78-mediated chemoresistance, and Akt phosphorylation were abrogated by inhibition of CLPTM1L. These findings demonstrate a novel and potentially targetable mechanism of cytoprotection and chemoresistance in pancreatic tumors.

Identification of Novel Biomarkers in Pancreatic Tumor Tissue to Predict Response to Neoadjuvant Chemotherapy

“…The top four biomarkers for NAC resistance, namely, GRP78, CADM1, PGES2, and RUXF demonstrated very high predictive ability for chemo-resistance with AUROC > 0.92. Notably, GRP78 has been previously demonstrated to play an important role in mediating chemoresistance in PDAC (15)(16)(17). Moreover, RUXF and PGES2 are known to be involved in chemo-resistance in ovarian and colorectal cancer, respectively (18,19).…”

GRP78 targeting: Hitting two birds with a stone

“…Alternatively, the proapoptotic action of the UPR could be compensated by the activation of the Akt/PI3K pathway, resulting in cell survival. The extracellular loop of Cleft Lip and Palate Transmembrane 1-Like (CLPTM1L) is essential for gemcitabine resistance and interaction with GRP78 [ 51 ]. Additionally, natural products such as isoliquiritigenin, a chalcone-type flavonoid, were able to reduce the chemoresistance and colony-forming ability of oral squamous cell carcinomas [ 52 ].…”

Targeting the GRP78 Pathway for Cancer Therapy

“…With the development of research and technology, it is believed that GRP78 may have obvious therapeutic potential as a target (55,56). Both GRP78 itself and other forms of GRP78 have a unique role in controlling cell survival and signal transduction, which is developing into an excellent treatment tool for malignant tumors in the targeted treatment of some cancers, and is expected to be applied to other diseases.…”