Deciphering the role of RINT-1 in regulating pancreatic ductal adenocarcinoma (PDAC) homeostasis

Introduction:

RINT-1 (RAD50-interacting protein 1) is a multifunctional protein playing a role in cell cycle regulation, genomic stability, telomere maintenance, ER-Golgi trafficking and autophagy. Beside facilitating cellular homeostasis, rare missense mutation found in RINT-1 and overexpression of RINT-1 were associated to increase the risk of development of different kind of tumors including breast cancer, colorectal cancer, and Lynch-syndrome type cancers.

Aims & Methods:

To characterize more in details the mechanisms of RINT-1 regulation and to ultimately identify RINT1-dependent pathways that could be targeted in PDAC, an extensive interaction study through yeast-two hybrid assay and mass spectrometry was preliminary performed.

Results:

We discovered hundreds of new RINT1-interaction partners including E3 ligases interacting with RINT-1 allowing a better understanding of RINT-1 biological function. In addition, we identify several post-translational modifications including ubiquitination and sumoylation and demonstrated that ubiquitination is a key regulator of RINT-1 stability and biological function. Hereby, we show that RINT-1-depletion in PDAC cell lines leads to severe growth defects in vitro and in vivo associated with massive Golgi fragmentation and G2 cell cycle arrest followed by ER-stress and autophagy. Complete collapse of cellular homeostasis finally results in activation of apoptosis. In addition, subcutaneous xenografts showed strong infiltration of B220+ immune cells in RINT- 1-deficient tumors.

Conclusion:

These data suggest that RINT-1 homeostasis is essential for PDAC survival and represents therefore a putative therapeutic target. Altogether, these data reveal the key role of RINT-1 in PDAC homeostasis.