Abstract
The combination of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) with subsidiary agents is a promising anticancer strategy to conquer TRAIL resistance in malignant cells. Glipizide is a second-generation oral hypoglycemic medicine for the cure of type II diabetes because of its capability to selectively stimulate insulin secretion from β-cells. In this study, we revealed that glipizide could trigger TRAIL-mediated apoptotic cell death in human lung adenocarcinoma cells. Pretreatment with glipizide downregulation of p-Akt and p-mTOR in different concentrations. In addition, LC3-II and p-Akt was suppressed in the presence of LY294002, a well-known inhibitor of P13K. Treatment with glipizide commenced in a slight increase in conversion rate of LC3-I to LC3-II and significantly decreased p62 expression levels in a dose-dependent manner. This indicates that glipizide encouraged autophagy flux activation in human lung cancer cells. Inhibition of autophagy flux applying a specific inhibitor and genetically modified ATG5 siRNA enclosed glipizide-mediated enhancing effect of TRAIL. These data demonstrate that inhibition of Akt/mTOR by glipizide sensitizes TRAIL-induced tumor cell death through activating autophagy flux and also suggest that glipizide may be a combination therapeutic target with TRAIL protein in TRAIL-resistant cancer cells.
Highlights
Lung cancer is the principle cause of cancerconcerned death in the world with over one million men and women diagnosed each year
Treatment of glipizide or tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) alone did not or only slightly influenced cell death (Figure 1) and did not morphological change was recognized compared with that in control, suggesting that A549 cells were highly resistant to TRAILmediated apoptosis
Co-treatment with TRAIL and different concentrations of glipizide significantly increased the number of apoptotic cell deaths or going through apoptosis compared to glipizide or TRAIL alone (Figures 1A, 1B, 1C, and 1D)
Summary
Lung cancer is the principle cause of cancerconcerned death in the world with over one million men and women diagnosed each year. Multiple options for the cure of lung cancer have been described, including radiation therapy, chemotherapy, and surgery [1, 2]. Combination chemotherapy can be dynamic for patients with advanced cancers that are not adaptable to surgical treatment or radiation therapy. Tumor necrosis factor (TNF)-related apoptosisinducing ligand is a type II transmembrane cytokine. It is a member of the TNF superfamily, and mediates cellular apoptosis in a wide extent of tumor cells. TRAIL can bind up to five members of the death receptor family: The death receptors (DR4, DR5), the decoy receptors (DcR1, DcR2) and osteoprotegerin (OPG) [5, 6]. TRAIL initiates apoptosis upon binding of death receptors DR4 and DR5 leads to the recruitment of Fas-associated death domain protein and consummately procaspase-8, to the construction of death-inducing signaling complex (DISC), leading to consequent effector caspases (caspase-8, -9, -10, and -3) [8, 9]
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