Distinct Metabolic Signature of Human Bladder Cancer Cells Carrying an Impaired Fanconi Anemia Tumor-Suppressor Signaling Pathway

Abstract

Metabolic profiling has great potential to help the diagnosis and prognosis of cancer patients. Fanconi Anemia (FA) tumor suppressor signaling has been instrumental in understanding human-tumorigenesis. However, this instrumental understanding has never been demonstrated at the metabolic level. Here we show that impaired FA signaling can lead cells to exhibit metabolic signatures of tumorigenesis. This is consistent with our original studies of the roles of FA signaling in suppressing non-FA tumorigenesis at functional and genetic levels. Using ultra-performance liquid chromatography-mass spectroscopy and gas chromatography-mass spectrometry, we characterized metabolic alterations in bladder cancer cells carrying an intact or impaired FA pathway. The latter was obtained by ectopically expressing FAVL (FAVL-high), which we previously found to be capable of inactivating FA signaling. 18 metabolites, end products of cell proliferation and/or apoptosis, were significantly different between FAVL-high and -low cells. Methionine, phenylalanine and threonine, resulting from a tumorigenic process, were substantially increased in FAVL-high cells. With this study, we achieved genomic, functional, and metabolomic characterization on roles of FA signaling in the development of human cancer. Furthermore, this study provides novel insights into how to translate FA basic research into strategies for producing effective biomarkers in human cancer diagnosis and prognosis.

Fanconi Anemia Signaling and Cancer

“…As accumulated studies have indicated, malfunctioned FA genes and proteins have been found to be associated with a variety of cancer patients who do not have FA (Table 1). For the first time, our studies have evidently shown that an impaired FA pathway is associated with the development of human cancer, and the altered pathway can promote the development of non-FA human cancer[18–21]. These findings further support the general tumor suppressor roles played by the FA proteins.…”

“…As a result, 18 metabolites, which represent the end products of cell proliferation and/or apoptosis, were found to be significantly different between FAVL-high and -low cells. Methionine, phenylalanine and threonine, resulting from a tumorigenic process, were substantially increased in FAVL-high cells (FA signaling compromised cells) [21]. With this study, characterization on the tumor-promotion roles of aberrant FA signaling in the development of human cancer in the general population was achieved at the genomic, functional, as well as the metabolic levels.…”

A new look at molecular biology of breast cancer

“…Following the functional demonstration of impaired FA signaling contributing to the development of human cancer in patients without FA, [41][42][43] the genetics and metabolomics studies further confirmed this unique role in promoting formation of human cancers, 40,44,45 including breast cancer, for the general population. BRCAs are widely accepted to be important tumor suppressors before the term of the (canonical) FA signaling pathway, which was seemingly fine for studying their individual roles in DNA damage repair.…”

Involvement of FANCD2 in Energy Metabolism via ATP5α

“…This marked us being the first to have achieved characterization of the general tumor suppressor functions of the FA signaling pathway at all three levels, genetically 46 , functionally 47 as well as metabolically 45 . The significance of FA signaling is further supported by the occurrence of the impaired FA pathway in human cancers, in which there is about 30–50% of tumors carrying a defective signaling network at the genetic level alone.…”