Stress granules in colorectal cancer: Current knowledge and potential therapeutic applications

Table 1 Expression and prognostic value of stress granule-associated proteins in colorectal cancer

Components	Role in SG	mRNA expression in tumors (GEPIA)	Expression in CRC patients (literature)	Overall survival (GEPIA)	Overall survival (Human Protein Atlas)
G3BP1	Promotes SG assembly	Up	Unknown	No significant difference	Better prognosis with high expression
G3BP2	Promotes SG assembly	Up	Unknown	No significant difference	Better prognosis with high expression
USP10	Promotes SG assembly	Up (trend)	Down in 18.6% of patients[47]	No significant difference	Better prognosis with high expression
CAPRIN1	Promotes SG assembly	Up	Unknown	No significant difference	Better prognosis with high expression
UBAP2L	Promotes SG assembly	No significant difference	Unknown	No significant difference	No significant difference
TIA1	Promotes SG assembly	Down (trend)	sTIA1 (spliced variant) is Up[171]	Poor prognosis with high expression	Better prognosis with high expression
TIAL1	Promotes SG assembly	Down (trend)	Unknown	Poor prognosis with high expression	No significant difference
DDX3	Promotes SG assembly	No significant difference	Poor prognosis with high expression[57]	No significant difference	Better prognosis with high expression
PABP1	Promotes SG assembly	Up	Unknown	NA	No significant difference
FMR1	Promotes SG assembly	No significant difference	Unknown	No significant difference	Better prognosis with high expression
PDCD4	Promotes SG assembly	Down (trend)	Down[172]	No significant difference	No significant difference
ATXN2	Promotes SG assembly	No significant difference	Unknown	No significant difference	No significant difference
ANG	Promotes SG assembly	No significant difference	Up	No significant difference	No significant difference
ZFP36	Promotes SG clearance and SG-P-Bodies fusion	Down	Down[26]	Poor prognosis with low expression (P = 0.16: trend)	No significant difference
ZFP36L1	Promotes SG-P-Bodies fusion	Down	Unknown	No significant difference	No significant difference
ELAVL1	mRNA stabilization	Up (trend)	Up[26]	No significant difference	Better prognosis with high expression
CUGBP2	mRNA stabilisation	No significant difference	Down[173]	No significant difference	Better prognosis with high expression
MSI-1	Promotes SG assembly	No significant difference	Up[54]	No significant difference	No significant difference
KHSRP	Unknown	No significant difference	Unknown	No significant difference	No significant difference
BAG3	Promotes SG clearance	No significant difference	Up[174]	No significant difference	Poor prognosis with high expression
PRMT1	Inhibition of SG formation	Up (trend)	(Poor prognosis with high expression[119]	Better prognosis with high expression (not significant: marked trend)	Better prognosis with high expression
PRMT5	Inhibition of SG formation	Up (trend)	Up[175]	Better prognosis with high expression (not significant: marked trend	Better prognosis with high expression
HDAC6	Promotes SG assembly	Down	Up[176]	Poor prognosis with high expression (not significant: marked trend	Poor prognosis with high expression
SIRT6	Promotes SG assembly	No significant difference	Down[113]	No significant difference	No significant difference
EP300	Inhibition of SG formation	No significant difference	Up[105]	No significant difference	No significant difference
JMJD6	Promotes SG assembly	No significant difference	Up[121]	No significant difference but marked trend for a poor prognosis with high expression	No significant difference
CK2	Inhibition of SG formation	Up (trend)	Up[177]	No significant difference	Poor prognosis with high expression
PRKAA1 (AMPK)	Promotes SG assembly	No significant difference	Up[126,127]	No significant difference	Better prognosis with high expression
MTOR	Unclear	No significant difference	mTORC1 Up[122]	No significant difference	No significant difference
TARDBP	Promotes SG assembly	No significant difference	Unknown	No significant difference	No significant difference
RBFOX2	Regulation of cell cycle	Down	Up[101]	No significant difference	No significant difference
RACK1	Regulation of apoptosis	Up		No significant difference	No significant difference
ULK1	Promotes SG disassembly	Down	Up[178] (Poor Prognosis)	No significant difference	Poor prognosis with high expression
ULK2	Promotes SG disassembly	Down	Down[179]	No significant difference	No significant difference
VCP	Promotes SG disassembly	No significant difference	Up (poor prognosis with high expression)[180]	No significant difference	No significant difference

The differential mRNA expression of stress granule proteins in colorectal cancer as compared to matched non-tumoral tissues were retrieved from the GEPIA database (http://gepia.cancer-pku.cn/detail; normal tissues: n = 349; tumors: n = 275) and compared with published studies. Survival analyses were retrieved from the GEPIA (cutoff-High: 80%; cutoff-Low: 20%) and the Human Protein Atlas Database (https://www.proteinatlas.org) using the best separation method between low and high expression of protein candidates. SG: Stress granule; NA: Not available.

Table 2 Potential therapeutic approaches to impair stress granule function in cancer cells

Strategies	Target	Models	Known impact on SGs	Anticancer effect on CRC	Clinical trials for CRC (ID)
Targeting proteins involved in SG assembly
EGCG	G3BP1	Lung cancer[146]	Reduction of SG assembly	Yes[181]	NCT02891538; NCT02321969; NCT01239095
Resveratrol	G3BP1	CRC[145]	Unknown	Yes[145]	NCT00433576; NCT00920803
GAP161 peptide	G3BP1	CRC[43]	Unknown	Yes[43]	None
RK-33	DDX3	CRC[182]	Unknown	Yes[182]	None
Targeting G4DNA/RNA structures
EMICORON	G4DNA	CRC[147]	Unknown	Yes[147]	None
chANG	angiogenin	CRC[148]	Unknown	Yes[148]	None
(mAb), 26-2F	angiogenin	CRC[149]	Unknown	Yes[149]	None
Targeting AMPK/mTORC1 axis
Compound C	AMPK	Yeast[151] CRC[152]	Impairs SG assembly in yeast[151]	Yes[152]	None
Rapamycin	mTORC1	CRC[183]	Unknown	Yes[183]	NCT00409994; NCT03439462
Everolimus	mTORC1	Breast[16]	SG inhibition	Yes[184]	NCT01154335; NCT00419159; NCT01387880
Temsirolimus	mTORC1	CRC[185]	Unknown	Yes[185]	NCT00593060; NCT00827684; NCT01183663
Targeting HDACS/SIRTs
OSS_128167	SIRT6	Pancreas cancer[161]	Unknown	Unknown	No
A-452	HDAC6	CRC[158]	Unknown	Yes[158]	None
C1A	HDAC6	CRC[157]	Unknown	Yes[157]	None
ACY-1215	HDAC6	CRC[108]	Unknown	Yes[108]	None
MPT0G612	HDAC6	CRC[159]	Unknown	Yes[159]	None
Targeting SGs-associated RNA-binding proteins controlling cancer-related factors
MS-444	HuR	CRC[166]	Unknown	Yes[166]	None
DHTS	HuR	CRC[186]	Unknown	Yes[186]	None
Resveratrol	RBFOX2	CRC[101]	Unknown	Yes[101]	NCT00433576; NCT00920803
Targeting microtubules
Paclitaxel	Microtubules	Green monkey kidney fibroblasts (CV-1 cells)[153]	Promotes SG formation	Yes[187]	NCT00598247; NCT00024401; NCT00667641
Vinblastine	Microtubules	Green monkey kidney fibroblasts (CV-1 cells)[153]	Prevents SG assembly	Yes[188]	None

Several approaches can be used to efficiently reduce stress granule assembly and their oncogenic activities. This table provides some examples for each strategy. Some of them have been tested in colorectal cancers models and others have reached clinical trials (https://clinicaltrials.gov/). SG: Stress granule; CRC: Colorectal cancer.