Survivin antagonizes chemotherapy-induced cell death of colorectal cancer cells

Abstract

Irinotecan (CPT-11) and oxaliplatin (L-OHP) are among the most frequently used drugs against colorectal tumors. Therefore, it is important to define the molecular mechanisms that these agents modulate in colon cancer cells. Here we demonstrate that CPT-11 stalls such cells in the G2/M phase of the cell cycle, induces an accumulation of the tumor suppressor p53, the replicative stress/DNA damage marker γH2AX, phosphorylation of the checkpoint kinases ATM and ATR, and an ATR-dependent accumulation of the pro-survival molecule survivin. L-OHP reduces the number of cells in S-phase, stalls cell cycle progression, transiently triggers an accumulation of low levels of γH2AX and phosphorylated checkpoint kinases, and L-OHP suppresses survivin expression at the mRNA and protein levels. Compared to CPT-11, L-OHP is a stronger inducer of caspases and p53-dependent apoptosis. Overexpression and RNAi against survivin reveal that this factor critically antagonizes caspase-dependent apoptosis in cells treated with CPT-11 and L-OHP. We additionally show that L-OHP suppresses survivin through p53 and its downstream target p21, which stalls cell cycle progression as a cyclin-dependent kinase inhibitor (CDKi). These data shed new light on the regulation of survivin by two clinically significant drugs and its biological and predictive relevance in drug-exposed cancer cells.

A ZEB1/p53 signaling axis in stromal fibroblasts promotes mammary epithelial tumours

“…6c, d; right panels). Although ZEB1 did not affect the mRNA expression of p53 , deletion of ZEB1 in CAFs markedly increased p21 mRNA levels while remarkably decreasing expression of survivin , a p53-repressed gene 33 (Supplementary Fig. 6a).…”

Prognostic Value of BIRC5 in Lung Adenocarcinoma Lacking EGFR, KRAS, and ALK Mutations by Integrated Bioinformatics Analysis

“…Thr117 is a key site on the regulation of proliferation and cell cycle, and Thr34 is involved in cell apoptosis [37]. BIRC5 has been identified as a critical target involved in a variety of cancer cell signaling pathways, and the upregulation of BIRC5 may serve as a role in the following mechanisms: critically antagonizing caspase-dependent apoptosis and activating P53 and its downstream target P21, which stalls cell cycle progression as a cyclin-dependent kinase inhibitor (CDKi) [38]. Additionally, BIRC5 promotes the migration and invasion of tumor cells mediated by the TGF- β pathway [39] and the PI3K/AKT pathway [25], interacts with proteins associated with DNA damage repair [40], and regulates tumor cell proliferation mediated via the β -catenin pathway [41].…”

Obatoclax, a Pan-BCL-2 Inhibitor, Downregulates Survivin to Induce Apoptosis in Human Colorectal Carcinoma Cells Via Suppressing WNT/β-catenin Signaling

“…Along this line, in this report we, for the first time, identified survivin as a novel molecule targeted by Obatoclax to induce apoptosis. Notably, given both survivin and antiapoptotic BCL-2 proteins represent two integral branches of pro-survival mechanisms that promote therapeutic resistance of cancer cells, our discovery that Obatoclax downregulates survivin aside from inhibiting anti-apoptotic BCL-2 proteins is clinically attractive regarding the use of Obatoclax to facilitate drug sensitization in cancer cells with inherent or acquired resistance to cancer therapeutics [16,26,39,40].…”

“…Functionally, survivin is essential for mitosis, particularly during the metaphase-anaphase transition, acts as an apoptosis inhibitor, and promotes cell migration, angiogenesis, and cancer stemness maintenance. As expected, survivin upregulation is highly associated with pathogenesis, resistance to chemo-and radiotherapies, and poor prognosis for a variety of human malignancies, including CRC [12][13][14][15][16][17][18]. Hence, considering the cancer-selective expression pattern and pivotal role of survivin in cancer pathogenesis, targeting survivin represents a promising approach for developing novel cancer therapeutics [19,20].…”