Abstract
Lung cancer, especially lung adenocarcinoma, is one of the main causes of death worldwide. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a primary anticancer agent and a member of the tumor necrosis factor family that selectively induces apoptosis in various tumor cells, but not in normal cells. Combination chemotherapy can be used for treating specific cancer types even at progressive stages. In the present study, we observed that 5-fluorouracil, which exerts anticancer effects by inhibiting tumor cell proliferation, enhanced TRAIL-induced apoptosis of TRAIL-resistant human adenocarcinoma A549 cells. Interestingly, 5-fluorouracil treatment markedly increased Bax and p53 levels and 5-fluorouracil and TRAIL cotreatment increased Ac-cas3 and Ac-cas8 levels compared with those in control cells. Taken together, the present study demonstrated that 5-fluorouracil enhances TRAIL-induced apoptosis in TRAIL-resistant lung adenocarcinoma cells by activating Bax and p53, and also suggest that TRAIL and 5-fluorouracil cotreatment can be used as an adequate therapeutic strategy for TRAIL-resistant human cancers.
Highlights
Lung cancer, especially lung adenocarcinoma, is one of the main causes of death worldwide [1]
The present study demonstrated that 5-fluorouracil enhances Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in TRAIL-resistant lung adenocarcinoma cells by activating Bax and p53, and suggest that TRAIL and 5-fluorouracil cotreatment can be used as an adequate therapeutic strategy for TRAIL-resistant human cancers
Our results showed that TRAIL and 5-fluorouracil cotreatment increased Ac-cas3 and Ac-cas8 expression gradually (Figure 2D). These results suggest that 5-fluorouracil enhances the apoptosis of TRAIL-resistant human lung adenocarcinoma A549 cells
Summary
Especially lung adenocarcinoma, is one of the main causes of death worldwide [1]. TRAIL activation induces apoptotic pathway by stimulating TRAIL receptors (TRAIL-R1 and TRAIL-R2; known as death receptors 4 and 5 [DR4 and DR5], respectively) on the surface of target cells [9]. Binding of TRAIL to the death receptors DR4 and DR5 recruits Fas-associated death domain protein and eventually procaspase-8 to form a death-inducing signaling complex on the inner surface of the plasma membrane of cancer cells, which in turn leads to caspase-8 activation [11, 12]. Apoptosis is induced by the intrinsic apoptotic pathway, which is usually activated by endogenous stresses such as DNA damage, hypoxia, or other cellular stresses, and the extrinsic apoptotic pathway, which is induced by cell surface death receptors such as TNF receptor superfamily [21, 22]. We investigated molecular mechanisms underlying the anticancer effect of 5-fluorouracil and the synergistic effect of 5-fluorouracil and TRAIL cotreatment on TRAIL-resistant A549 cells
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