Divergent control of Cav-1 expression in non-cancerous Li-Fraumeni syndrome and human cancer cell lines

Abstract

Li-Fraumeni syndrome (LFS) is primarily characterized by development of tumors exhibiting germ-line mutations in the p53 gene. Cell lines developed from patients of a LFS family have decreased p53 activity as evidenced by the absence of apoptosis upon etoposide treatment. To test our hypothesis that changes in gene expression beyond p53 per se are contributing to the development of tumors, we compared gene expression in non-cancerous skin fibroblasts of LFS-affected (p53 heterozygous) vs. non-affected (p53 wild-type homozygous) family members. Expression analysis showed that several genes were differentially regulated in the p53 homozygous and heterozygous cell lines. We were particularly intrigued by the decreased expression (~88%) of a putative tumor-suppressor protein, caveolin-1 (Cav-1), in the p53-mutant cells. Decreased expression of Cav-1 was also seen in both p53-knockout and p21-knockout HTC116 cells suggesting that p53 controls Cav-1 expression through p21 and leading to the speculation that p53, Cav-1 and p21 may be part of a positive auto-regulatory feedback loop. The direct relationship between p53 and Cav-1 was also tested with HeLa cells (containing inactive p53), which expressed a significantly lower Cav-1 protein. A panel of nonfunctional and p53-deficient colon and epithelial breast cancer cell lines showed undetectable expression of Cav-1 supporting the role of p53 in the control of Cav-1. However, in two aggressively metastasizing breast cancer cell lines, Cav-1 was strongly expressed suggesting a possible role in tumor metastasis. Thus, there is a divergent control of Cav-1 expression as evidenced in non-cancerous Li-Fraumeni syndrome and some aggressive human cancer cell lines.

Bioinformatics analysis of aggressive behavior of breast cancer via an integrated gene regulatory network

“…[31] Recent studies have also shown that CAV1 depletion is strictly TP53 dependent through the AMP-activated protein kinase (AMPK)-TP53/p53 signaling. [32,33] The evidence confirmed the existence of the miR222-CAV1-TP53 regulation which was predicted in the network. Therefore, the regulatory relation between CAV1 and the linked miRNAs such as miR-101 and miR-128 in the network, as well as the linked TFs of E2F4 and SP1, might exist in the aggressive breast cancer cell.…”

Gemcitabine enhances the transport of nanovector-albumin-bound paclitaxel in gemcitabine-resistant pancreatic ductal adenocarcinoma

“…As an example, HRAS or ABL1-induced oncogenic transformation of mouse fibroblasts caused the transcriptional downregulation of cav-1 (37, 38). In another work, mutations in TP53 gene, encoding p53, resulted in a reduced expression of cav-1 (39). Studies in prostate cancer cells have shown that cav-1 expression can be induced by protein kinase C ε (PKC ε ) through the sequential activation of mitogen-activated protein kinases (MAPK), c-Myc, and androgen receptor (40).…”

Caveolae and signalling in cancer

“…In addition, CAV1 and p53 are co-regulated by a feedforward loop. Reduced CAV1 expression is observed in cells from individuals with Li-Fraumeni syndrome, which is caused by mutations in TP53 (which encodes p53) 101 . Conversely, CAV1 induces p53 activation 97 .…”