Figure 8

Proposed signaling pathways. Proposed pathways whereby the combination of α-TEA + doxorubicin (DOXO) or α-TEA + cisplatin (CDDP) induces apoptosis in p53 mutant, triple-negative MDA-MB-231 and BT-20 human breast cancer cells. p73 can be activated via multiple mechanisms and pathways, including: c-Abl and JNK can directly phosphorylate p73 to stabilize it; Yap in nucleus can bind with p73 to enhance its transcriptional activity and stability; and p73 can be transcriptionally regulated (not studied here). Yap can be regulated in a positive manner by c-Abl via phosphorylation enhancing its stability and transcriptional activity, and in a negative manner by Akt via inhibiting translocation of Yap into the nucleus. c-Abl can directly phosphorylate JNK and JNK can enhance c-Abl nuclear translocation. Therefore, c-Abl, JNK and Yap play positive roles and Akt plays a negative role in p73 activation. Our data show that DNA-damaging drugs DOXO and CDDP activated c-Abl and JNK, but also activated Akt, which can counteract c-Abl and JNK effects on activation of p73. Combination treatments not only act cooperatively to activate c-Abl and JNK, but also act cooperatively to inhibit pAkt and pYap (ser-127), leading to Yap nuclear translocation and p73 activation. In summary, combinations of α-TEA + DOXO or α-TEA + CDDP act cooperatively to upregulate c-Abl/JNK, induce Yap nuclear translocation and downregulate pAkt/pYap, leading to activation of p73 and upregulation of p73-mediated pro-apoptotic factors mediators, and downregulation of Bcl-2, thereby restoring DOXO and CDDP chemotherapeutic potential in p53 mutant, triple-negative breast cancers. DR5, death receptor 5.