Cysteine-rich intestinal protein 1 suppresses apoptosis and chemosensitivity to 5-fluorouracil in colorectal cancer through ubiquitin-mediated Fas degradation

Abstract

Background Cysteine-rich intestinal protein 1 (CRIP1) is highly expressed in human intestine and aberrantly expressed in several types of tumor. However, studies on CRIP1 are limited and its role on tumor development and progression remains controversial and elusive. Methods Immunohistochemistry was performed to evaluate the expression of CRIP1 in paired normal and colorectal tumor specimens, as well as colorectal cell lines. Functional assays, such as CCK8, TUNEL assay and in vivo tumor growth assay, were used to detect the proliferation, apoptosis and response to 5-FU of CRIP1. Western blot was used to analyze Fas-mediated pathway induced by CRIP1. Rescue experiments were performed to evaluate the essential role of CRIP1 for Fas-mediated apoptosis. Results We demonstrated that CRIP1 is overexpressed in CRC tissues compared with adjacent normal mucosa. CRIP1 could dramatically recover the 5-Fluorouracil (5-FU) inhibited CRC cell proliferation in vitro and stimulate the tumor formation of CRC in vivo, probably through inhibiting CRC cell apoptosis. Moreover, CRIP1 also dramatically recovered the 5-Fluorouracil (5-FU) induced tumor cell apoptosis in vitro . Further study demonstrated that CRIP1 down-regulated the expression of Fas protein and proteins related to Fas-mediated apoptosis. CRIP1 could interact with Fas protein and stimulate its ubiquitination and degradation. In addition, a negative correlation was detected between the expression of CRIP1 and Fas protein in most of the clinical human CRC samples. Conclusion The current research reveals a vital role of CRIP1 in CRC progression, which provide a novel target for clinical drug resistance of colorectal cancer and undoubtedly contributing to the therapeutic strategies in CRC. Electronic supplementary material The online version of this article (10.1186/s13046-019-1117-z) contains supplementary material, which is available to authorized users.

CRIP1 cooperates with BRCA2 to drive the nuclear enrichment of RAD51 and to facilitate homologous repair upon DNA damage induced by chemotherapy

“…Here we identified CRIP1 as a new posttranscriptional modifier of RAD51. However, in contrast to the findings of Zhang et al [ 11 ] that CRIP1 promotes ubiquitination and degradation of Fas, exogenous overexpression of CRIP1 dramatically inhibited RAD51 ubiquitination levels, suggesting that CRIP1 itself does not possess ubiquitin ligase activity. The regulatory effect of CRIP1 on protein ubiquitination levels is indirect and mainly depends on the protease activity of ubiquitinases or deubiquitinases regulated by CRIP1.…”

“…Cysteine-rich intestinal protein 1 (CRIP1), a member of the LIM/double-zinc finger protein family, is overexpressed and associated with prognosis in several tumor types [ 7 – 11 ]. However, its functional role functional role of CRIP1 in cancer biology is poorly understood.…”

The Ubiquitin Gene Expression Pattern and Sensitivity to UBB and UBC Knockdown Differentiate Primary 23132/87 and Metastatic MKN45 Gastric Cancer Cells

“…Apoptosis is a tightly controlled process, characterized by three pathways, namely, the mitochondrial [ 28 ], endoplasmic reticulum [ 51 ] and death receptor signaling pathways [ 28 ]. Interestingly, Zhang et al have demonstrated, in several cancer cell lines, that the oncoprotein Cysteine-rich intestinal protein 1 (CRIP1) can interact with Fas, enhancing its ubiquitination and degradation and leading to inhibition of caspases 8 and 3, thus underlining the tumor suppressor role of this transmembrane protein [ 52 ].…”

Human lung tissue resident memory T cells are re-programmed but not eradicated with systemic glucocorticoids after acute cellular rejection

“…The role of CRIP1 expression after successful treatment is similarly unknown. CRIP1 is a zinc-binding protein with high expression in immune cells and epithelium that may play a role in DNA damage repair 18,37,38 . Its role in allograft recovery after ACR requires further study.…”