Nuclear IGF1R interact with PCNA to preserve DNA replication after DNA-damage in a variety of human cancers

PLoS One. 2020 Jul 23;15(7):e0236291. doi: 10.1371/journal.pone.0236291. eCollection 2020.

Abstract

Nuclear IGF1R has been linked to poor outcome in cancer. We recently showed that nuclear IGF1R phosphorylates PCNA and increases DNA damage tolerance. In this paper we aimed to describe this mechanism in cancer tissue as well as in cancer cell lines. In situ proximity ligation assay identified frequent IGF1R and PCNA colocalization in many cancer types. IGF1R/PCNA colocalization was more frequently increased in tumor cells than in adjacent normal, and more prominent in areas with dysplasia and invasion. However, the interaction was often lost in tumors with poor response to neoadjuvant treatment and most metastatic lesions. In two independent cohorts of serous ovarian carcinomas and oropharyngeal squamous cell carcinomas, stronger IGF1R/PCNA colocalization was significantly associated with a higher overall survival. Ex vivo irradiation of ovarian cancer tissue acutely induced IGF1R/PCNA colocalization together with γH2AX-foci formations. In vitro, RAD18 mediated mono-ubiquitination of PCNA during replication stress was dependent on IGF1R kinase activity. DNA fiber analysis revealed that IGF1R activation could rescue stalled DNA replication forks, but only in cancer cells with baseline IGF1R/PCNA interaction. We believe that the IGF1R/PCNA interaction is a basic cellular mechanism to increase DNA stress tolerance during proliferation, but that this mechanism is lost with tumor progression in conjunction with accumulated DNA damage and aberrant strategies to tolerate genomic instability. To exploit this mechanism in IGF1R targeted therapy, IGF1R inhibitors should be explored in the context of concomitant induction of DNA replication stress as well as in earlier clinical stages than previously tried.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cell Nucleus / metabolism*
  • DNA Damage*
  • DNA Replication*
  • Humans
  • Neoplasm Grading
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Neoplasms / therapy
  • Proliferating Cell Nuclear Antigen / metabolism*
  • Protein Binding
  • Receptor, IGF Type 1 / metabolism*
  • Survival Analysis

Substances

  • IGF1R protein, human
  • Proliferating Cell Nuclear Antigen
  • Receptor, IGF Type 1

Associated data

  • figshare/10.6084/m9.figshare.12388256

Grants and funding

This work is supported by the Swedish Cancer Society, the Swedish Childhood Cancer Foundation, The Cancer Society in Stockholm, the Stockholm County Council and the China Scholarship Council [CSC201706370014] and Karolinska Institutet.