Functional role and therapeutic potential of the pim-1 kinase in colon carcinoma

Neoplasia. 2013 Jul;15(7):783-94. doi: 10.1593/neo.13172.

Abstract

Purpose: The provirus integration site for Moloney murine leukemia virus 1 (Pim-1) kinase is overexpressed in various tumors and has been linked to poor prognosis. Its role as proto-oncogene is based on several Pim-1 target proteins involved in pivotal cellular processes. Here, we explore the functional relevance of Pim-1 in colon carcinoma.

Experimental design: RNAi-based knockdown approaches, as well as a specific small molecule inhibitor, were used to inhibit Pim-1 in colon carcinoma cells. The effects were analyzed regarding proliferation, apoptosis, sensitization toward cytostatic treatment, and overall antitumor effect in vitro and in mouse tumor models in vivo.

Results: We demonstrate antiproliferative, proapoptotic, and overall antitumor effects of Pim-1 inhibition. The sensitization to 5-fluorouracil (5-FU) treatment upon Pim-1 knockdown offers new possibilities for combinatorial treatment approaches. Importantly, this also antagonizes a 5-FU-triggered Pim-1 up-regulation, which is mediated by decreased levels of miR-15b, a microRNA we newly identify to regulate Pim-1. The analysis of the molecular effects of Pim-1 inhibition reveals a complex regulatory network, with therapeutic Pim-1 repression leading to major changes in oncogenic signal transduction with regard to p21(Cip1/WAF1), STAT3, c-jun-N-terminal kinase (JNK), c-Myc, and survivin and in the levels of apoptosis-related proteins Puma, Bax, and Bcl-xL.

Conclusions: We demonstrate that Pim-1 plays a pivotal role in several tumor-relevant signaling pathways and establish the functional relevance of Pim-1 in colon carcinoma. Our results also substantiate the RNAi-mediated Pim-1 knockdown based on polymeric polyethylenimine/small interfering RNA nanoparticles as a promising therapeutic approach.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Apoptosis / genetics
  • Cell Line, Tumor
  • Cell Proliferation
  • Colonic Neoplasms / drug therapy
  • Colonic Neoplasms / genetics*
  • Colonic Neoplasms / metabolism*
  • Disease Models, Animal
  • Drug Resistance, Neoplasm / genetics
  • Fluorouracil / pharmacology
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Knockdown Techniques
  • Humans
  • Mice
  • MicroRNAs / genetics
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Proto-Oncogene Proteins c-pim-1 / antagonists & inhibitors
  • Proto-Oncogene Proteins c-pim-1 / genetics*
  • Proto-Oncogene Proteins c-pim-1 / metabolism*
  • RNA, Small Interfering / genetics
  • Signal Transduction
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • MIRN15 microRNA, human
  • MicroRNAs
  • Protein Kinase Inhibitors
  • RNA, Small Interfering
  • Proto-Oncogene Proteins c-pim-1
  • Fluorouracil