The Mechanism and Therapeutic Potential of Targeting the Ninjurin Pathway for Tumors Carrying Wild-Type p53

Project Summary/Abstract
The tumor suppressor p53 is often referred to as the “guardian of the genome”. Mutations of the p53
gene occur in ~50% of human cancer and loss of p53 function is known to play a central role in tumor
progression and metastasis. Upon exposure to a stress signal, such as DNA damage, p53 transcription
factor is activated and then induces an array of pro-survival and pro-death genes. Due to its potent role
in tumor suppression, p53 is an attractive target for the development of new anticancer drugs. Nerve
injury-induced protein 1 (Ninjurin1, NINJ1) and NINJ2 constitute the Ninjurin family of cell adhesion
molecules and have been implicated in various pathological processes such as immune response.
However, the role of NINJ1 and NINJ2 in tumorigenesis is unclear. We showed previously that NINJ1
is a target of p53 and in turn represses p53 mRNA translation. Thus, NINJ1 and p53 forms a negative
feedback loop. Notably, our pilot study showed that NINJ1 and NINJ2 interact with each other through
their N-terminal extracellular domains. We also found that like NINJ1, NINJ2 forms a negative
regulatory loop with p53. To determine the biological significance of the NINJ1-NINJ2-p53 loop, we
showed that: (1) loss of NINJ1 or NINJ2 inhibits cell migration and formation of tumor spheres and
colonies in breast cancer cells and promote cellular senescence in mouse embryonic fibroblasts in a p53-
dependent manner; (2) mice deficient in Ninj1 or Ninj2 are prone to chronic inflammation, which is
likely due to enhanced pyroptosis through wild-type p53-dependent activation of NLRP3
inflammasome; (3) two small peptides, called Pep-1A and Pep-2A derived from N-terminal alpha helix
domain of NINJ1 and NINJ2 protein were able to disrupt the formation of NINJ1-NINJ2 complex and
elicit growth suppression. These observations prompt us to hypothesize that both NINJ1 and NINJ2
play a critical role in tumorigenesis through the p53 pathway. To test this, we will determine: (1) the
feedback regulatory loops between NINJ1 and NINJ2 and between p53 and the Ninjurin family; (2) the
biological significance of the NINJ1-NINJ2-p53 loop in tumor suppression; (3) whether the Ninj1-
Ninj2-p53 loop can be targeted to kill tumor cells carrying wild-type p53.

Grant Number: 5R01CA272753-04
NIH Institute/Center: NIH
Principal Investigator: Xinbin Chen