RETRACTED ARTICLE: JNK confers 5-fluorouracil resistance in p53-deficient and mutant p53-expressing colon cancer cells by inducing survival autophagy

Abstract

Deficiency or mutation in the p53 tumor suppressor gene commonly occurs in human cancer and can contribute to disease progression and chemotherapy resistance. Currently, although the pro-survival or pro-death effect of autophagy remains a controversial issue, increasing data seem to support the idea that autophagy facilitates cancer cell resistance to chemotherapy treatment. Here we report that 5-FU treatment causes aberrant autophagosome accumulation in HCT116 p53−/− and HT-29 cancer cells. Specific inhibition of autophagy by 3-MA, CQ or small interfering RNA treatment targeting Atg5 or Beclin 1 can potentiate the re-sensitization of these resistant cancer cells to 5-FU. In further analysis, we show that JNK activation and phosphorylation of Bcl-2 are key determinants in 5-FU-induced autophagy. Inhibition of JNK by the compound SP600125 or JNK siRNA suppressed autophagy and phosphorylation of c-Jun and Bcl-2 but increased 5-FU-induced apoptosis in both HCT116 p53−/− and HT29 cells. Taken together, our results suggest that JNK activation confers 5-FU resistance in HCT116 p53−/− and HT29 cells by promoting autophagy as a pro-survival effect, likely via inducing Bcl-2 phosphorylation. These results provide a promising strategy to improve the efficacy of 5-FU-based chemotherapy for colorectal cancer patients harboring a p53 gene mutation.

MEK5/ERK5 signaling inhibition increases colon cancer cell sensitivity to 5-fluorouracil through a p53-dependent mechanism

“…For instance, inhibition of MEK1/2 enhanced the radiosensitizing effects mediated by 5-FU in vitro and in vivo [45]. Further, JNK activity has been reported to prompt autophagy, protecting colon cancer cells with impaired p53 function from 5-FU cytotoxic effects, which in turn was shown to be reversed following JNK inhibition [46]. Instead, the p38MAPK pathway was shown to be activated in response to 5-FU, controlling cell fate by shifting the balance between apoptosis and autophagy towards increased 5-FU sensitivity [47].…”

Paxillin is positively correlated with the clinicopathological factors of colorectal cancer, and knockdown of Paxillin improves sensitivity to cetuximab in colorectal cancer cells

“…In the past few years, researchers have focused on the relationship among apoptosis, drug resistance and autophagy in cancer cells. Various studies have demonstrated that increased induction of autophagy can become a mechanism of allowing tumor cells to survive the conditions of hypoxia, acidosis or chemotherapy, which results in a decrease in apoptosis and drug resistance (24,25). There are also other studies indicating out that autophagy inhibitors in combination with chemotherapeutic agents may provide a premise for the treatment of colorectal cancer (26)(27)(28).…”

Mechanism of autophagic regulation in carcinogenesis and cancer therapeutics

“…For example, in response to irinotecan, pro-survival autophagy was induced by activating MAPK14/p38 signaling, which lead to drug resistance [108]. It is likely that protective autophagy in 5-FU resistance occurs through JNK activation [109]. Additionally, bortezomib and enzalutamide, which are androgen receptor signaling inhibitors (ARSIs), activate AMPK-dependent autophagy and provide therapeutic resistance [110,111].…”