Mitochondrial uncoupling protein 2 regulates the effects of paclitaxel on Stat3 activation and cellular survival in lung cancer cells

Abstract

Growing evidence suggests that Stat3 contributes to chemoresistance. However, the impact of chemotherapy on Stat3 activity is unclear. We found that paclitaxel activated Stat3 in the human lung cancer cell lines PC14PE6AS2 (AS2) and H157, whereas it reduced Stat3 activation in A549 and H460 cells. Pretreatment of AS2 and H157 cells with rotenone, an inhibitor of mitochondrially produced reactive oxygen species (ROS), or carbonyl cyanide p-(trifluoromethoxy)-phenylhydrazone (FCCP), a mitochondrial uncoupler, suppressed the paclitaxel-induced activation of Stat3. Uncoupling protein 2 (UCP-2), located in the inner membrane of the mitochondria, can reduce ROS production in conditions of oxidative stress. UCP-2 protein expression in the four cancer cell lines was higher than that in normal lung epithelial cells (NL-20), but its expression was lower in AS2 and H157 cells relative to A549 and H460 cells. Silencing high UCP-2 expression with small interfering RNA (siRNA) in A549 and H460 cells restored paclitaxel-induced Stat3 activation. In addition, paclitaxel-induced Stat3 activation led to the upregulation of survivin and Mcl-1, which in turn facilitated cell survival. Moreover, the CL1-5 subline had lower UCP-2 expression relative to the parental CL1-0 cells. Treatment with paclitaxel activated Stat3 in CL1-5 but not in CL1-0 cells, whereas in CL1-5 cells, the overexpression of UCP-2 with complementary DNA (cDNA) blocked Stat3 activation. In lung cancer patients, low UCP-2 expression in cancer cells was a predictor of a poor response to chemotherapy. Therefore, UCP-2 modulates the ROS/Stat3 signaling pathway and response to chemotherapy treatment in lung cancer cells. Targeting UCP-2, ROS and Stat3 pathways may improve anticancer therapies.

Exceedingly Higher co-loading of Curcumin and Paclitaxel onto Polymer-functionalized Reduced Graphene Oxide for Highly Potent Synergistic Anticancer Treatment

“…Although Cur possesses good ROS scavenging ability, in GP-Cur hybrid system Cur acts as a pro-oxidant by bringing cellular redox changes resulting in the accumulation of ROS, which consequently lead to cell death44. On the contrary, Ptx is reported to induce only a small amount of ROS due to the presence of a negative regulator of a mitochondrial ROS called UCP-245. Hence, in the synergistic GP-Cur-Ptx system, Cur acts as an antioxidant which may have an adverse effect on the anticancer drug, Ptx which then acts on tumor cells by increasing the ROS level to induce cell death46.…”

Ionizing radiation, ion transports, and radioresistance of cancer cells

“…In particular, over-expression of UCP2 has been reported in leukemia as well as in breast, colorectal, ovarian, bladder, esophagus, testicular, kidney, pancreatic, lung, and prostate cancer (Ayyasamy et al, 2011; Su et al, 2012). In human colon cancer, UCP2 mRNA and protein expression reportedly is increased by factor of 3–4 as compared to peritumoral normal epithelium.…”

“…In specimens of human ovarian cancers carboplatin/paclitaxel-resistant cancers showed decreased UCP2 protein abundances as compared to the sensitive ones (Pons et al, 2012). Likewise, progression-free and overall survival of patients with inoperable lung cancer who received cisplatin-based chemotherapy was higher when tumors expressed high levels of UCP2 as compared to tumors with low UCP2 levels (Su et al, 2012). A possible explanation of the latter observation is that especially in lung tumors with mutated p53, cisplatin elicits oxidative stress that induces pro-survival signaling.…”

“…A possible explanation of the latter observation is that especially in lung tumors with mutated p53, cisplatin elicits oxidative stress that induces pro-survival signaling. High UCP2 expression, however, diminishes cisplatin-evoked oxidative stress and, in turn, decreases the pro-survival signals (Su et al, 2012). …”

The role of mitochondrial bioenergetics and reactive oxygen species in coronary collateral growth

“…Third, activation of p53 favors transcription of target genes involved in oxidative phosphorylation, so inhibition of p53 by UCP-2 would further promote a shift in metabolism from mitochondrial respiration toward glycolysis (65). Fourth, translocation of p53 to initiate the intrinsic apoptotic cascade was blocked by uncoupling effect of FCCP, whereas UCP-2 knockdown promotes this translocation in JB6 cells (59). Overall, these data support the notion that UCP-2 promotes cancer growth not only through inhibition of oxidative stress via reduced mitochondrial ROS production but also by inhibiting key tumor suppressor functions mediated by p53.…”