# Non-genetic inactivation of caspase-3 and P53 increases cancer cell fitness by PDIA4 redistribution

## TL;DR

This study reveals how cancer cells resist chemotherapy by redistributing PDIA4, which inhibits cell death and promotes cancer cell survival.

## Contribution

A novel non-genetic mechanism involving PDIA4 redistribution to inhibit caspase-3 and p53, leading to chemoresistance in cancer cells.

## Key findings

- ER stress and UPR activation are necessary for chemoresistance to cisplatin and doxorubicin.
- PDIA4 redistribution to the cytosol inhibits caspase-3 and p53, increasing cancer cell proliferation.
- High PDIA4 and DNAJB12 expression in colorectal cancer tumors correlates with UPR induction.

## Abstract

Numerous cellular pathways are known to cause resistance in cancer cells. The unfolded protein response (UPR), a signaling pathway activated during proteostasis stress in the endoplasmic reticulum (ER), is an adaptive process to increase cancer cell fitness. However, the molecular mechanism between ER stress, UPR activation, and chemoresistance is insufficiently understood. Here, we report that ER stress induction and UPR activation are necessary for chemoresistance to cisplatin and doxorubicin. Mild ER stress is a sufficient precondition for cancer cells to evade cisplatin- and doxorubicin-associated cell death. Mechanistically, ER stress induction results in the redistribution of PDIA4 from the ER to the cytosol, facilitated by the c-tail-anchored proteins DNAJB12 and DNAJB14 and the cytosolic HSC70-cochaperone SGTA. In the cytosol, PDIA4 forms an inhibitory interaction with caspase-3 and wt-p53, leading to their attenuation and increased cancer cell proliferation. Furthermore, we show that PDIA4 must originate from the ER to inhibit caspase-3 and wt-p53 in the cytosol. Silencing PDIA4, DNAJB12/14, or SGTA rescues wt-p53 and caspase-3 activity. Finally, we found that in tumors isolated from colorectal cancer patients, PDIA4 and DNAJB12 are highly expressed compared to their healthy tissues; this expression is associated with the induction of the UPR. Our data show a novel non-genetic mechanism to inhibit apoptosis and suggest PDIA4, DNAJB12/14, and SGTA as novel therapeutic targets to rescue apoptosis and inhibit proliferation in cancer cells.