Translocation of IGF-1R in endoplasmic reticulum enhances SERCA2 activity to trigger Ca2+ER perturbation in hepatocellular carcinoma

The well-known insulin-like growth factor 1 (IGF1)/IGF-1 receptor (IGF-1R) signaling pathway is overexpressed in many tumors, and is thus an attractive target for cancer treatment. However, results have often been disappointing due to crosstalk with other signals. Here, we report that IGF-1R signaling stimulates the growth of hepatocellular carcinoma (HCC) cells through the translocation of IGF-1R into the ER to enhance sarco-endoplasmic reticulum calcium ATPase 2 (SERCA2) activity. In response to ligand binding, IGF-1Rβ is translocated into the ER by β-arrestin2 (β-arr2). Mass spectrometry analysis identified SERCA2 as a target of ER IGF-1Rβ. SERCA2 activity is heavily dependent on the increase in ER IGF-1Rβ levels. ER IGF-1Rβ phosphorylates SERCA2 on Tyr990 to enhance its activity. Mutation of SERCA2-Tyr990 disrupted the interaction of ER IGF-1Rβ with SERCA2, and therefore ER IGF-1Rβ failed to promote SERCA2 activity. The enhancement of SERCA2 activity triggered Ca2+ER perturbation, leading to an increase in autophagy. Thapsigargin blocked the interaction between SERCA2 and ER IGF-1Rβ and therefore SERCA2 activity, resulting in inhibition of HCC growth. In conclusion, the translocation of IGF-1R into the ER triggers Ca2+ER perturbation by enhancing SERCA2 activity through phosphorylating Tyr990 in HCC.

Activation of insulin-like growth factor-1 receptor (IGF-1R) promotes growth of colorectal cancer through triggering the MEX3A-mediated degradation of RIG-I

Insulin-like growth factor-1 receptor (IGF-1R) has been made an attractive anticancer target due to its overexpression in cancers. However, targeting it has often produced the disappointing results as the role played by cross talk with numerous downstream signalings. Here, we report a disobliging IGF-1R signaling which promotes growth of cancer through triggering the E3 ubiquitin ligase MEX3A-mediated degradation of RIG-I. The active β-arrestin-2 scaffolds this disobliging signaling to talk with MEX3A. In response to ligands, IGF-1Rβ activated the basal βarr2 into its active state by phosphorylating the interdomain domain on Tyr64 and Tyr250, opening the middle loop (Leu130‒Cys141) to the RING domain of MEX3A through the conformational changes of βarr2. The models of βarr2/IGF-1Rβ and βarr2/MEX3A could interpret the mechanism of the activated-IGF-1R in triggering degradation of RIG-I. The assay of the mutants βarr2Y64A and βarr2Y250A further confirmed the role of these two Tyr residues of the interlobe in mediating the talk between IGF-1Rβ and the RING domain of MEX3A. The truncated-βarr2 and the peptide ATQAIRIF, which mimicked the RING domain of MEX3A could prevent the formation of βarr2/IGF-1Rβ and βarr2/MEX3A complexes, thus blocking the IGF-1R-triggered RIG-I degradation. Degradation of RIG-I resulted in the suppression of the IFN-I-associated immune cells in the TME due to the blockade of the RIG-I-MAVS-IFN-I pathway. Poly(I:C) could reverse anti-PD-L1 insensitivity by recovery of RIG-I. In summary, we revealed a disobliging IGF-1R signaling by which IGF-1Rβ promoted cancer growth through triggering the MEX3A-mediated degradation of RIG-I.

Animal models of cancer metastasis / 国际肿瘤学杂志

Animal models using for research the cancer matestasis should be entirely similar to the clinical pathological process in patients.Currently,two kinds of animal models with genetic engineering and human tumor xenografts are available in laboratory,which provide a possible research tool to investigate the mechanism of tumor metastasis and explore the experimental treatment.In these models,the techniques including how to select the cell lines and using real-time imaging detection are very important factors.

Animal models of lung cancer / 国际肿瘤学杂志

In order to make a rational and effective cure measure for lung cancer,people need to establish suitable animal model.Spontaneous or induced model needs long time to form tumor and the rate is not steady.Xenograft mouse model is widely used in laboratories because of its steady tumor formation rate and less time in oncogenesis.Engineered mouse model which is based on genetic technology not only helps us to understand pathological process of lung cancer,but also can provide an ideal preclinical model of targeted therapy experiment,and it will be the important development direction of lung cancer animal model.

Aminopeptidase N and its inhibitors and carcinoma / 国际肿瘤学杂志

Aminopeptidase N,a zinc-dependent exopeptidase,is highly expressed in many kinds of tumors,which involves in the degradation of extracellular matrix barriers and angiogenesis and promotes the invasion and metastasis of cancer cells.Aminopeptidase N inhibitors can induce apoptosis and inhibit the invasion and metastasis of tumor cells,which has become an attractive target for anti-tumor therapy.

Reactive oxygen species and tumor therapy / 国际肿瘤学杂志

Oxidative stress can achieve the purpose of tumor therapy by accelerating the death of tumor cells.As a major molecule generated from the body's oxidative stress reaction,reactive oxygen species(ROS)exerts the antitumor efforts by promoting apoptosis,necrosis and autophagy.The drugs which could increase the level of ROS in cells have received more and more people's attention,and this provide a new research direction for the clinical treatment of tumors.

Des-γ-carboxy prothrombin in hepatocellular carcinoma / 国际肿瘤学杂志

Des-γ-carboxy prothrombin (DCP)is produced abnormally in hepatocellular carcinoma cells. Vitamin K utilizing deficiency and the decreasing activity of vitamin K-dependent γ-glutamyl carboxylate and coenzyme may involve in production of DCP. The enzymes in bepatocellular carcinoma cells are failed in carboxylating all the ten glutamic acid residues in amino- terminus of prothrombin precursor to Gla and make the difference between DCP and prothrombin. DCP is considered to be the marker for diagnosis of hepatocellular carcinoma. DCP might also be one of the growth-promoting factors to carcinoma cells. Therefore, inhibition of DCP in hepatocellular carcinoma cells is considered to be the therapeutic method of blocking hepatocellular car-cinoma growth. Vitamin K and its analogs are found to have the functions of inhibiting hepatocellular carcinoma cell producing DCP. The mechanism may relate to the increase of γ-glutamyl carboxylase activity.

Clinical study on the effect of Yangyinjiandu decoction on acute raditation esophagitis / 中华放射肿瘤学杂志

Objective To investigate the effect of Yangyinjiandu decoction for acute radiation esophagitis.Methods Lung cancer and mediastinal tumor treated by radiotherapy(portals including oesophagus to a radical tumoricidal dose≥40Gy, with≥10cm oesophagus include in radiotherapy).Patients were randomly divided according to the time of acceptance into the treatment group and the control group.All parameters of the two groups were basically similar and comparable.The treatment group was given Yangyinjiandu decoction(one dose daily,water decoction,200ml,twice a day) taken in the morning and in the evening before the end of radiotherapy.The control group was given oral vitamin C tablet 100mg once a day before the end of radiotherapy.Five days after radiotherapy,the control group took oral prednisone 5mg three times a day and amoxicillin 5g three times a day.All the above medicines were continued for 7 days.Results The commencement of complication was 14.86?0.34 days in the treatment group and 13.55?0.26 days in the control group(P

Nasopharyngeal hemorrhage after radiotherapy of nasopharyngeal carcinoma / 中华放射肿瘤学杂志

Objective To evaluate the incidence of nasopharyngeal hemorrhage after radiotherapy of nasopharyngeal carcinoma (NPC) in order to adjust adequately the dose of fractionated stereotactic radiosurgery (FSRS). Methods Eighteen NPC patients were treated by FSRS following conventional radiotherapy of D T65～74?Gy. Of them, 5 patients (T 4) with uncontrolled lesions received a boost dose of 24～40?Gy/6～8 f and 13 patients (T 2～3 ) with local recurrence received their second course of treatment with different regimens. Group A: 8 patients received routine radiotherapy 30～40?Gy followed by FSRS 24～30?Gy/6～9 f; Group B: 5 patients received FSRS 40～42?Gy/6～8 f alone. Results The frequency of nasopharyngeal hemorrhage was 3/5 for skull base invasion (T 4 ) lesions. The incidence of morbidity for re radiation after local recurrence of T 2～3 tumor was 1/8 in Group A and 1/5 in Group B.Conclusions The frequency of nasopharyngeal hemorrhage is high in skull base invasion by NPC (T 4).Therefore the dose of FSRS combined with conventional radiotherapy should be limited when re treating local recurrence of NPC.

Three-dimensional conformal radiation therapy for elderly non-small cell lung cancer patients / 中华放射肿瘤学杂志

Objective To study the role of three-dimensional conformal radiation therapy(3DCRT) in the treatment of elderly non-small cell lung cancer(NSCLC) patients.Methods From 2000 to 2004,39 elderly NSCLC patients(range 70-87 years) were treated by 3DCRT.Their Karnovsky performance score was 50-60 in 20 patients and those of the other 19 patients were not less than 70.Prescription dose were 40-60?Gy,with a median of 50?Gy.Results Thirty-six(92%) patients'symptoms were relieved at the end of treatment,with the other three patients' symptoms steady.Complete response and partial response was achieved in 19 and 17 patients respectively.The 1-year survival rate was 60%,with a median survival time of 10 months.Conclusions Three dimensional conformal radiotherapy is effective for elderly NSCLC patients in terms of symptom relief.For treatment choice of these senior NSCLC patients,the balance between tumor control and quality of life should be carefully considered.

CLINICAL OBSERVATION IN HYPOXY-RADIOTHERAPY OF LUNG CANCER / 中华放射肿瘤学杂志

From July 1991 to December 1993, 58 patients with Nonsmall cell lung cancer were randomly divided into hypoxyradiotherapy group (32 patients) and radiotherapy alone group (26 patients). Both groups received the sme radiotherapy with radiation dose of D T 65～70 to cancer of lungs. In hypoxia group, 10.5% oxygen gas mixture was inhaled during the therapy per session. The results showed that tumor response rates, immediate survival rates, skin and systemic reactions were similar in both groups. Hemogram was normal in both groups. In the hypoxyradiotherapy group, radioreaction of lungs, esophagus and trachea were milder than radiotherapy alone group (P

The studies of the pharmacodynamics of antineoplaston A_(10) / 中国药理学通报

This paper describes the inhibitory effects of antineoplaston A10 with using different dosages against the mouse S180, rats W256 and Bca - P6 and MGC cell (human) in nude mouse. When the administered dosage of oral formulation antineoplaston A10 was 4000mg ? kg-1 ? 24h-1 against the S180 for 10d . inhibitory rate was 32. 5%( P