Systematic analysis of NLMP suggests nuclear localization of RTK/MET kinases resemble cancer cell clearance

Yingqiu Xie, Ayan A Nurkesh, Nazgul Ibragimova, Zhuldyz Zhanzak, Aizhan Meyerbekova, Zhanna Alexeyeva, Aiya Yesbolatova, Madina Satayeva, Aidana Mustafa, Limara Manarbek, Aisulu Maipas, Akerke Altaikyzy, Zhibek Keneskhanova, Burkitkan Akbay, Zhenbang Chen

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)

Abstract

BACKGROUND: Some membrane proteins can translocate into the nucleus, defined as nuclear localized membrane proteins (NLMPs), including receptor tyrosine kinases (RTKs). We previously showed that nuclear MET (nMET), a member of RTKs, mediates cancer stem-like cells self-renewal to promote cancer recurrence. However, it is unknown that nMET or mMET, which is the ancestor in the evolution of cancer cell survival and clearance. Here, we aim to study the NLMP functions in cell death, differentiation and survival.

METHOD: We applied the systematic reanalysis of functional NLMP and clinical investigations of nMET from databases. In addition, we used soft agar assay, immunoblotting, flow cytometry, and immunofluorescence confocal microscopy for examinations of nMET functions including stem-like cell formation, cell signaling, cell cycle regulation, and co-localization with regulators of cell signaling. ShRNA, antibody of recognizing surface membrane MET based treatment were used to downregulate endogenous nMET to uncover its function.

RESULTS: We predicted and demonstrated that nMET and nEGFR are most likely not ancestors. nMET overexpression induces both cell death and survival with drug resistance and stem cell-like characters. Moreover, the paradoxical function of nMET in both cell death and cell survival is explained by the fact that nMET induces stem cell-like cell growth, DNA damage repair, to evade the drug sensitization for survival of single cells while non-stem cell-like nMET expressing single cells may undergo clearance by cell death through cell cycle arrest induced by p21.

CONCLUSION: Taken together, our data suggest a link between nuclear RTK and cancer cell evolutionary clearance via cell death, and drug resistance for survival through stemness selection. Targeting evolved nuclear RTKs in cancer stem cells would be a novel avenue for precision cancer therapy.

Original languageEnglish
Pages (from-to)43
JournalJournal of Experimental and Clinical Cancer Research
Volume38
Issue number1
DOIs
Publication statusPublished - Jan 30 2019

Keywords

  • Apoptosis
  • Cell Nucleus/genetics
  • Cell Proliferation
  • Drug Resistance, Neoplasm
  • Humans
  • Neoplasms/genetics
  • Neoplastic Stem Cells/metabolism
  • Proto-Oncogene Proteins c-met/genetics
  • Receptor Protein-Tyrosine Kinases/genetics
  • Signal Transduction
  • Tumor Cells, Cultured

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