Beyond Cell Death – Antiapoptotic Bcl-2 Proteins Regulate Migration and Invasion of Colorectal Cancer Cells In Vitro

Abstract

Migration and invasion of malignant cells are prerequisites for cancer progression and metastasis. The Bcl-2 family of proteins consists of about 25 members and has been extensively studied in the context of apoptosis. Despite the fact that small molecules targeting Bcl-2 proteins have already entered clinical trials, very few studies investigated a role of antiapoptotic Bcl-2 proteins beside cell death in the context of metastasis. The aim of this study was to dissect a potential role of the antiapoptotic Bcl-2 proteins Mcl-1, Bcl-2 and Bcl-xL on migration and invasion of colorectal cancer cells independent of their cell death control function. We used migration and invasion assays as well as three dimensional cell cultures to analyze colorectal cancer cell lines (HT29 and SW480) after siRNA mediated knockdown or overexpression of Mcl-1, Bcl-2 or Bcl-xL. We observed neither spontaneous cell death induction nor impaired proliferation of cells lacking Mcl-1, Bcl-2 or Bcl-xL. In contrast, knockdown of Mcl-1 led to increased proliferation. Strikingly, we demonstrate a profound impairment of both, migration and invasion, of colorectal cancer cells after Mcl-1, Bcl-2 or Bcl-xL knockdown. This phenotype was completely revised in cells overexpressing Mcl-1, Bcl-2 or Bcl-xL. The most pronounced effect among the investigated proteins was observed for Bcl-2. The data presented indicate a pivotal role of Mcl-1, Bcl-2 and Bcl-xL for migration and invasion of colorectal cancer cells independent of their known antiapoptotic effects. Thus, our study illustrates novel antitumoral mechanisms of Bcl-2 protein targeting.

Prolyl Hydroxylase 3 Attenuates MCL-1–Mediated ATP Production to Suppress the Metastatic Potential of Colorectal Cancer Cells

“…This unique function, which goes beyond the antiapoptotic activity of full-length MCL-1 protein, makes MCL-1 indispensable for the survival of cancer cells (26,40). Furthermore, MCL-1 reportedly enhances the migratory and invasive potential of colorectal tumor cells, independently from its antiapoptotic effects (25,31). Consistently, we observed that improved ATP production, as well as enhanced migration and invasion of PHD3-deficient tumor cells, could be reverted by simultaneous knockdown of MCL-1.…”

“…Among other molecules (and HIF in particular, see below), we focused on MCL-1, a BCL-2 family member, which is expressed in colorectal cancer (24,25). MCL-1 protein undergoes proteolytic cleavage.…”

Autophagy in colorectal cancer: An important switch from physiology to pathology

“…A recent report suggested that the prosurvival Bcl2 protein modulates autophagy only indirectly, by inhibiting the apoptosis mediators Bax and Bak [103] . Bcl2 has been associated with migration and invasion of malignant cells and with the prevention of apoptosis in pT3 CRC patients [104,105] . In addition, the overexpression of Bcl2 in CRC was correlated with resistance to paclitaxel [106] .…”

Prodigiosin isolated from cell wall of Serratia marcescens alters expression of apoptosis-related genes and increases apoptosis in colorectal cancer cells

“…Among anti-apoptotic genes, expression of survivin and Bcl-2 genes contributes to determine the resistance of a majority of colon tumor cells to chemotherapy, tumorigenesis and poor prognosis [7,8]. Expression of survivin and Bcl-2 has been shown to be up-regulated in colorectal cancer [7,9]. These genes are overexpressed in the most human cancers but rarely in normal tissues [7,8].…”