Par3L enhances colorectal cancer cell survival by inhibiting Lkb1/AMPK signaling pathway

Biochem Biophys Res Commun. 2017 Jan 22;482(4):1037-1041. doi: 10.1016/j.bbrc.2016.11.154. Epub 2016 Nov 28.

Abstract

Partitioning defective 3-like protein (Par3L) is a recently identified cell polarity protein that plays an important role in mammary stem cell maintenance. Previously, we showed that high expression of Par3L is associated with poor survival in malignant colorectal cancer (CRC), but the underlying mechanism remained unknown. To this end, we established a Par3L knockout colorectal cancer cell line using the CRISPR/Cas system. Interestingly, reduced proliferation, enhanced cell death and caspase-3 activation were observed in Par3L knockout (KO) cells as compared with wildtype (WT) cells. Consistent with previous studies, we showed that Par3L interacts with a tumor suppressor protein liver kinase B1 (Lkb1). Moreover, Par3L depletion resulted in abnormal activation of Lkb1/AMPK signaling cascade. Knockdown of Lkb1 in these cells could significantly reduce AMPK activity and partially rescue cell death caused by Par3L knockdown. Furthermore, we showed that Par3L KO cells were more sensitive to chemotherapies and irradiation. Together, these results suggest that Par3L is essential for colorectal cancer cell survival by inhibiting Lkb1/AMPK signaling pathway, and is a putative therapeutic target for CRC.

Keywords: AMPK pathway; CRISPR/Cas; Colorectal cancer; Lkb1; Par3L.

MeSH terms

  • AMP-Activated Protein Kinase Kinases
  • AMP-Activated Protein Kinases / metabolism*
  • Apoptosis
  • Base Sequence
  • CRISPR-Cas Systems
  • Caco-2 Cells
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Proliferation
  • Cell Survival
  • Colon / metabolism
  • Colon / pathology
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / metabolism*
  • Colorectal Neoplasms / pathology*
  • Colorectal Neoplasms / therapy
  • Gene Editing
  • Gene Knockout Techniques
  • Humans
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mutation
  • Protein Serine-Threonine Kinases / metabolism*
  • Rectum / metabolism
  • Rectum / pathology
  • Signal Transduction*

Substances

  • Carrier Proteins
  • Membrane Proteins
  • PARD3B protein, human
  • Protein Serine-Threonine Kinases
  • STK11 protein, human
  • AMP-Activated Protein Kinase Kinases
  • AMP-Activated Protein Kinases