Abstract
Colon cancer is still the third most common cancer which has a high mortality but low five-year survival rate. Novel tyrosine kinase inhibitors (TKI) such as pazopanib become effective antineoplastic agents that show promising clinical activity in a variety of carcinoma, including colon cancer. However, the precise underlying mechanism against tumor is unclear. Here, we demonstrated that pazopanib promoted colon cancer cell apoptosis through inducing PUMA expression. Pazopanib induced p53-independent PUMA activation by inhibiting PI3K/Akt signaling pathway, thereby activating Foxo3a, which subsequently bound to the promoter of PUMA to activate its transcription. After induction, PUMA activated Bax and triggered the intrinsic mitochondrial apoptosis pathway. Furthermore, administration of pazopanib highly suppressed tumor growth in a xenograft model. PUMA deletion in cells and tumors led to resistance of pazopanib, indicating PUMA-mediated pro-apoptotic and anti-tumor effects in vitro and in vivo. Combing pazopanib with some conventional or novel drugs, produced heightened and synergistic antitumor effects that were associated with potentiated PUMA induction via different pathways. Taken together, these results establish a critical role of PUMA in mediating the anticancer effects of pazopanib in colon cancer cells and provide the rationale for clinical evaluation.
Highlights
Colon cancer makes major contribution to cancer mortality in the world [1, 2]
To explore whether p53 up-regulated modulator of apoptosis (PUMA) plays an important role in the response to pazopanib, we first detect PUMA expression in WT (HCT-116, RKO) and p53 mutant (HT29, DLD1) colon cancer cell lines
The mRNA level of PUMA was enhanced in colon cancer cells with different p53 statuses (Figure 1F), which is prior to PUMA protein accumulation
Summary
Colon cancer makes major contribution to cancer mortality in the world [1, 2]. significant improvement of therapeutic approach and the application of targeted therapy in past decades, median overall survival of patients with metastatic colon cancer is 2 years after chemotherapy [3, 4]. Colon cancer develops from the acquisition of genetic mutations, which leads the action of signals to eliminate apoptosis and confer resistance to drugs [5,6,7,8,9,10] In this regard, most clinical drugs for cancer therapy are chosen by their ability to induce apoptosis. Pazopanib has significantly prolonged progression-free survival (PFS) benefit in patients with advanced or metastatic carcinoma [21, 26, 27], which is widely established as first-line therapy with limited side-effects It has been used as a second-line therapy and showed clinical activity as well as tolerated after failure of other systemic treatments in advanced neuroendocrine tumor (NET) [28] as well as in non-small cell lung cancer (NSCLC) [29]. The mechanisms by which pazopanib exercise its antitumor activity especially how to induce cell apoptosis are poorly understood
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