Abstract: Plakophilin 3 (PKP3) is a desmosomal plaque protein whose loss leads to an increase in invasion, tumor formation, metastasis and radio-resistance 1-3. Further experiments demonstrated that the levels of lipocalin 2 (LCN2) were increased upon PKP3 loss and was required for the increase in tumor formation 4. We further demonstrated that the increase in LCN2 expression is required for the ability of the PKP3 knockdown clones to be resistant to γ-radiation, 5-fluorouracil (5FU) and doxorubicin, but not to paclitaxel. An analysis of the PKP3 knockdown cells post radiation demonstrates that loss of PKP3 leads to an increase in autophagy and a decrease in reactive oxygen species suggesting that one mechanism by which PKP3 may promote tumor progression is by promoting an increase in resistance to oxidative stress and the resultant DNA damage resulting from oxidative stress and that LCN2 might serve as a potential therapeutic target in radio and chemo resistant tumors.