Enhanced susceptibility to tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in oral squamous cell carcinoma cells treated with phosphatidylinositol 3-kinase inhibitors
Authors: Masaru Ohashi
Masao Nagumo
Hitoshi Watanabe
Makiko Uchida
Masayasu Iwase
Satoru Shintani
Sayaka Takaoka
Gen Kondo
Sayaka Yoshiba
Journal: International Journal of Oncology (2007)
Discipline: CLINICAL MEDICINE
Keywords: oral squamous cell carcinoma; TRAIL; phosphatidylinositol 3-kinase; Akt; apoptosis
Affiliations: Department of Oral and Maxillofacial Surgery, Showa University School of Dentistry, Tokyo, Japan.

Abstract:  In general, oral squamous cell carcinoma (OSCC) cells are relatively resistant to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis during culture in vitro. Here, we studied the role of phosphatidylinositol 3-kinase (PI 3-K)/Akt in survival and apoptosis of these cells. The PI 3-K inhibitors wortmannin and LY294002 markedly suppressed phosphorylation of Akt and accelerated TRAIL-mediated apoptosis in OSCC cells. Addition of TRAIL to PI 3-K inhibitor-treated cells resulted in caspase-8 activation and loss of mitochondrial membrane potential. Furthermore, inhibitors of caspase-3, -8 and -9 reduced the accelerative effect of PI 3-K inhibitors on TRAIL-mediated apoptosis. These results suggest that the pro-apoptotic effect of PI 3-K inhibitors on TRAIL-mediated apoptosis may contribute to both the extrinsic and intrinsic pathways. Although PI 3-K inhibitors did not affect expression of the TRAIL receptors DR4 and DR5, we observed a marked reduction in expression of cellular FLICE-inhibitory protein (c-FLIP), Bcl-2, cellular inhibitor of apoptosis protein-1 (cIAP-1) and X-linked IAP (XIAP), whereas Bax was up-regulated and no significant difference was observed in expression of Bcl-xL, Bak or cIAP-2. Therefore, the PI 3-K/Akt signaling pathway provides partial regulation of TRAIL-mediated apoptosis in OSCC cells via modulation of c-FLIP, Bcl-2, Bax, cIAP-1 and XIAP expression. These results suggest that PI 3-K inhibitors may represent a novel strategy for overcoming resistance to TRAIL-mediated apoptosis in OSCC cells. 

Retracted: No

PubPeer comments:
 The authors developed in this paper a neural network for prediction with extraordinary performance. The neural network has u201cone single parameteru201d to be determined by learning from data. However, **the description of such a neural network is confusing and inconsistent.** (a) In **Section 3.1**, the authors claimed that u201cthe number of neurons in the input layer is equal to the number of the entered HFEs $h_i(X) (i = 1, 2,u2026, n)$ in the learning samples.u201d Such a claim is very unusual because the input layer is associated with the number of arguments under consideration but **not with the size of training sample**. Besides, the illustration in Fig.1 shows an additional parameter $d$ as in $h_d(X)$. (b) In **Section 3.1**, the authors claimed that u201cthe number of neurons in the patter layer equals to the number of the learning samples, and **each neuron corresponds to a sample.**u201d According to this claim and eq.(2), the neural network proposed in this paper **simply records all the training samples**. Such a structure is very rarely used in neural networks not only because it leads to an unnecessarily large network but also because it typically results in poor generalization performance. (c) In **Section 3.2**, the authors claimed that a method called u201cfruit fly optimization algorithm with fast decreasing stepu201d is used to train the network. The method is illustrated in Fig. 2 with a two-dimensional scenario. However, as reported in Section 4.3, the whole neural network has **one and only one parameter $sigma$ to be determined**. A simple line search method solves the problem. Could the authors address these issues? ![file] ![file] ![file] ![file] ![file] ![file] ,