Role of retinoids in the prevention and treatment of colorectal cancer

Table 1 Summary of pathways dsyregulated in colorectal cancer and the effect of retinoids on these pathways in both colorectal cancer and other tumor types

Protein	Mutation rate	Result of gene mutation	Response to retinoid treatment
APC	80%[57,65]	Loss of β-catenin degradation[58]; constitutive activation of the Wnt/β-catenin pathway[59]; decreased RDH levels inhibiting formation of ATRA[42]	Not determined
β-Catenin	5%[56]	Loss of β-catenin degradation[56]; constitutive activation of the Wnt/β-catenin pathway[56]; increased CYP26A1 levels resulting in increased degradation of ATRA	Increased degradation of β-catenin via RXR-mediated pathway[23,24]
PI3K	30%-50%[77,78]	Activation of Akt and loss of GSK3β function[80,82]; increased cancer metastasis[88], partially through NF-κB activation and increased expression of MMP-2 and -9[87,89,90]; positive cell cycle progression through cyclin D1[105]; loss of cell-cell adhesion by Snail accumulation to repress E-cadherin[106]	Decrease MMP-2 and MMP-9 activity[28]; increase TIMP-1 expression[28]; decrease the phosphorylation of GSK3β, decrease cellular proliferation, and increase the expression of pro-apoptotic proteins in human leiomyoma and myometrial cells[115]; CRBP-I inhibits PI3K/Akt activation in breast cancer cells[116]; inhibit PI3K activity to decrease CRC cell invasion in vitro and metastasis in vivo[25]
PTEN	20%-40%[80]	Loss of PI3K/Akt inhibition[80]; correlation with tumor aggressiveness and invasiveness[109-111]	Suppression of cellular proliferation and enhanced apoptosis by increasing PTEN expression in smooth muscle cells, neuroblastoma and glioblastoma cells, promyelocytes, leukemia cells, fibroblasts, and breast, endometrial, and hepatocellular carcinoma cells[119-128]
COX-2	80%-90%[134-136]	Increased PGE2 signaling[133,137,138], ERK activation[140], PI3K/Akt signaling through increased EGFR[133,140,141], β-catenin stabilization[142,143], and MMP-2 and MMP-9 expression to promote cellular proliferation[144,145]	Decrease COX-2 expression[146], PGE2, β-catenin levels, and MMP-9[135,144]; inhibition of cell growth[151]; increased apoptosis and RARβ expression[152]
PPARγ	8%[161]	Loss of inhibitory action of gene transcription of pro-survival and growth amplification genes[155,162-165]; increased expression of COX-2[154]	Suppress COX-2 and MMP-7 expression and induction of cell cycle arrest and apoptosis[171]; induce expression of RARβ mRNA in breast cancer cells[175]; increase apoptosis in glioblastoma cells[176]; stimulate PTEN expression in leukemia cells and fibroblasts[121,128]
p53	50%[177,178]	Loss of anti-growth and apoptotic activity; loss of p53/Siah-1-mediated β-catenin degradation[187]	Increase retinyl ester storage through transcription of retSDR1[54]; enhance p53-mediated cell cycle inhibition and apoptosis through activation of AP-2α and p21 in breast cancer cells[192], caspases in keratinocytes[188], Btg2 and CRABP-II in breast cancer cells[191]; STRA6 induction in ovarian cancer cells, fibroblasts, and CRC cells[193]

APC: Adenomatous polyposis coli; RDH: Retinol dehydrogenase; ATRA: All-trans-retinoic acid; CYP26A1: Cytochrome P450 26A1; RXR: Retinoid X receptor; PI3K: Phosphatidylinositol-3-kinase; GSK3β: Glycogen synthase kinase 3β; NF-κB: Nuclear factor-kappa B; MMP: Matrix metalloproteinase; TIMP-1: Tissue inhibitor of matrix metalloproteinase 1; CRBP: Cellular retinol binding protein; CRC: Colorectal cancer; PTEN: Phosphatase and tensin homolog deleted on chromosome 10; COX2: Cyclooxygenase 2; PGE2: Prostaglandin E2; ERK: Extracellular signal-regulated kinase; EGFR: Epidermal growth factor receptor; RARβ: Retinoic acid receptor β; PPARγ: Peroxisome proliferator-activated receptor γ; AP-2α: Activator protein 2α; Btg2: Beta cell translocation gene 2; CRABP-II: Cellular retinoic acid binding protein II; STRA6: Stimulated by retinoic acid 6.