Targeting Differentially Expressed UPR Mediators in Mucin‐rich Colorectal Cancers and Conventional Colorectal Adenocarcinomas
Authors: Nakada Emily M. , Bruno Sierra R. , Miller Jill , Korwin‐Mihavics Bethany , Chamberlain Nicolas L. , Ramsey Jon , Zenali Maryam , Ades Steven , Anathy Vikas 
Published: June 2021

Background

Despite the improved 5‐year survival rate, colorectal cancer (CRC) is the second leading cause of cancer deaths in the United States and is sub‐classified according to mucin content as mucin‐rich CRC (MCRC, ≥50% mucin content) or conventional colorectal adenocarcinoma (CCRA, <50% mucin content). Ten percent of CRCs are considered mucin‐rich and are reported to be less sensitive to chemotherapy treatment than CCRAs. The unfolded protein response (UPR) is an adaptive response activated when unfolded proteins accumulate in the endoplasmic reticulum (ER). When the UPR is incapable of dealing with an increased protein load, it leads to apoptosis. Despite the increased protein load and UPR activation, tumor cells are known to maintain protein homeostasis and avoid apoptosis.

Objectives

We hypothesized that the higher protein load in MCRC cells, initiated by the high demand of producing mucins, induces greater ER stress and activation of the UPR. Here, we aimed to identify UPR markers uniquely upregulated in their expression in MCRC versus CCRA patient biopsies. We also utilized CRC cell lines with similar mucin and UPR profiles as the biopsies, to target differentially regulated UPR markers for inhibition as potential targets for CRC therapy.

Results

Our data showed that when compared to CCRA samples, MCRC biopsies express significantly higher mRNAs for several UPR markers such as IRE1α, XBP1, and CHOP, which significantly correlate (p<0.0001, p<0.0001, p=0.0003, respectively) with MUC6 expression. In contrast, CCRA samples expressed higher levels of several protein disulfide isomerases (PDIs) including PDIA1 (p=0.0001), PDIA3 (p<0.0001), PDIA5 (p<0.0001), and PDIA17 (p=0.0025), that are known to be the downstream of canonical transducers of the UPR. We also identified CCRA (Caco2) and MCRC (LS174T) cell lines with similar UPR profiles to the biopsies. Our data indicate that cells from the MCRC cell line were less responsive to LOC14, a PDI inhibitor, whereas the CCRA cell line, which expressed higher levels of several PDIs, were less proliferative and had a greater decrease in total cell numbers following 6 days of treatment with LOC14. Accordingly, treatment with LOC14 inhibited one of the PDIs, PDIA3 in the CCRA cell, but not the MCRC cell line.

Conclusions

These novel results suggest that CCRAs and MCRCs have different signatures of UPR markers and CCRAs may be more responsive to PDI inhibitors of the UPR than MCRCs. Further characterization of the UPR profiles of CCRAs and MCRCs could aid in the development of future anti‐cancer therapies and targeting of UPR transducers and their downstream mediators.

Support or Funding Information

NIH R01 HL122383 and Department of Pathology and Laboratory Medicine (UVM) Startup Fund (VA)

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.