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.
Highlights
Colorectal Carcinoma (CRC) is the second most common malignancy in women and the third in men worldwide with an increasing incidence
In order to investigate the expression of the antiapoptotic B-cell lymphoma-2 (Bcl-2) proteins Mcl-1, Bcl-2 and Bcl-xL in human CRC cell lines, we measured protein levels in four colorectal cancer cell lines
Mcl-1, Bcl-2 and Bcl-xL expression was detectable in CRC cell lines (Fig. 1A)
Summary
Colorectal Carcinoma (CRC) is the second most common malignancy in women and the third in men worldwide with an increasing incidence. CRC is the fourth common cause of death from cancer. Even if advances in drug development and surgery led to an increased overall survival, the prognosis of patients with metastasized CRC (stage UICC IV) is still limited [1,2]. Metastasation is a major cause of death in cancer patients and involves a multistep process of enormous complexity. The proapoptotic Bcl-2 proteins (i.e. Bax and Bak) are bound by their antiapoptotic relatives (i.e. Mcl-1, Bcl-2 and Bcl-xL). In case of a shift of this balance towards death, the proapoptotic Bcl-2 proteins are released by their antiapoptotic counterparts. Once the proapoptotic Bcl-2 proteins are set free, mitochondria become activated and cell death occurs [5]. Antiapoptotic Bcl-2 proteins act by sequestering proautophagic proteins such as Beclin1 [8,9]
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