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Aim: To compare endocrine characteristics of  endometrial cancer (EC) patients based on recent molecular EC types classification. Materials & methods: A total of 234 treatment-naive EC patients as well their tumors were studied. Results: Patients with POLE mutations demonstrated tendency to lower body mass index (BMI) and higher serum estradiol. Patients with p53 overexpression were older and had higher diabetes incidence. In the without characteristic molecular profile group there was no difference in fasting serum insulin, estradiol and testosterone levels between women with BMI ≥30.0 and <30.0. The mismatch repair deficient group patients had a tendency toward later menarche compared with the without characteristic molecular profile group one. Conclusion: Studied endocrine characteristics are associated with BMI or tumor molecular-biological type that might be relevant to EC genesis, course and prognosis. [ABSTRACT FROM AUTHOR]

The question hidden in the title of this manuscript (whether the topic develops or remains constant) is important for all areas of science. It is also a serious problem for endometrial cancer (EC) study. In recent times the incidence of EC gradually increases in parallel with obesity epidemics. The main point of this review was evaluation of changes in EC area in last few decades, which are not only seen in tumor incidence, but also in its biology, hormonal-metabolic characteristics of patients and in the ratio of risk and anti-risk factors. One can hope that data accumulated recently and summarized here under the notion of EC evolution will find its use for advancement of EC prevention and treatment. [ABSTRACT FROM AUTHOR]

Purpose: Adipose tissue products may contribute to endometrial cancer (EC) initiation and further growth that encourages the analysis of this issue in patients with different obesity phenotypes. Methods/patients: Omental fat depot characteristics were studied in EC patients (n = 57) with 'standard' (SO) or 'metabolically healthy' (MHO) obesity. Collected omental samples were evaluated by immunohistochemistry /IHC/ for brown fat marker UCP1, CYP19 (aromatase) and macrophage infiltration markers (CD68, CD163, crown-like structures/CLS) expression. Total RNA extracted from the same samples was investigated for UCP1, CYP19, PTEN and adipokine omentin mRNA. Results: Immunohistochemistry data revealed a statistically significant increase in aromatase and CD68 expression and tendency to increase of UCP1 expression in SO patients' omental fat compared to samples obtained from MHO patients. Additionally, positive correlation of EC clinical stage with UCP1 protein and its mRNA content in omental fat was pronounced in MHO as well as SO group, while with omentin mRNA it was discovered only in patients with SO. An inclination to the correlation with better tumor differentiation was seen for UCP1 and CD68 protein expression in patients with MHO and with worse (high grade) differentiation-for CD68 expression in the group with SO. Conclusions: In aggregate, this suggests that obesity phenotype has significant impact on omental fat tissue characteristics which is related to the clinical course of EC and may have practical consequences. [ABSTRACT FROM AUTHOR]

Thyroid cancer (TC) is the most common endocrine malignancy and its incidence has increased over the last few decades. As has been revealed by a number of studies, TC tissue's micro-RNA (miRNA) profile may reflect histological features and the clinical behavior of tumor. However, alteration of the miRNA profile of plasma exosomes associated with TC development has to date not been explored. We isolated exosomes from plasma and assayed their characteristics using laser diffraction particle size analysis, atomic force microscopy, and western blotting. Next, we profiled cancer-associated miRNAs in plasma exosomes obtained from papillary TC patients, before and after surgical removal of the tumor. The diagnostic value of selected miRNAs was evaluated in a large cohort of patients displaying different statuses of thyroid nodule disease. MiRNA assessment was performed by RT-qPCR. In total, 60 patients with different types of thyroid nodal pathology were included in the study. Our results revealed that the development of papillary TC is associated with specific changes in exosomal miRNA profiles; this phenomenon can be used for differential diagnostics. MiRNA-31 was found to be over-represented in the plasma exosomes of patients with papillary TC vs. benign tumors, while miRNA-21 helped to distinguish between benign tumors and follicular TC. MiRNA-21 and MiRNA-181a-5p were found to be expressed reciprocally in the exosomes of patients with papillary and follicular TC, and their comparative assessment may help to distinguish between these types of TC with 100 % sensitivity and 77 % specificity. [ABSTRACT FROM AUTHOR]

Metformin, a biguanide antidiabetic drug, is used to decrease hyperglycemia in patients with type 2 diabetes. Recently, the epidemiological studies revealed the potential of metformin as an anti-tumor drug for several types of cancer, including breast cancer. Anti-tumor metformin action was found to be mediated, at least in part, via activation of adenosine monophosphate-activated protein kinase (AMPK)-intracellular energy sensor, which inhibits the mammalian target of rapamycin (mTOR) and some other signaling pathways. Nevertheless, some patients can be non-sensitive or resistant to metformin action. Here we analyzed the mechanism of the formation of metformin-resistant phenotype in breast cancer cells and its role in estrogen receptor (ER) regulation. The experiments were performed on the ER-positive MCF-7 breast cancer cells and metformin-resistant MCF-7 subline (MCF-7/M) developed due to long-term metformin treatment. The transcriptional activity of NF-κB and ER was measured by the luciferase reporter gene analysis. The protein expression was determined by immunoblotting (Snail1, (phospho)AMPK, (phospho)IκBα, (phospho)mTOR, cyclin D1, (phospho)Akt and ERα) and immunohistochemical analysis (E-cadherin). We have found that: 1) metformin treatment of MCF-7 cells is accompanied with the stimulation of AMPK and inhibition of growth-related proteins including IκBα, NF-κB, cyclin D1 and ERα; 2) long-term metformin treatment lead to the appearance and progression of cross-resistance to metformin and tamoxifen; the resistant cells are characterized with the unaffected AMPK activity, but the irreversible ER suppression and constitutive activation of Akt/Snail1 signaling; 3) Akt/Snail1 signaling is involved into progression of metformin resistance. The results presented may be considered as the first evidence of the progression of cross-resistance to metformin and tamoxifen in breast cancer cells. Importantly, the acquired resistance to both drugs is based on the constitutive activation of Akt/Snail1/E-cadherin signaling that opens new perspectives to overcome the metformin/tamoxifen resistance of breast cancer. © 2016 IUBMB Life, 68(4):281-292, 2016 [ABSTRACT FROM AUTHOR]

Due to a number of reasons, endometrial cancer is a point of interest not only for oncologists, but also for a variety of specialists – especially endocrinologists. The endocrinology of endometrial cancer can be firmly divided into two categories – steroid and non-steroid. The steroid approach dominated during several decades due to hyperestrogenization signs observed in some patients. The balance was only regained in the last 15 years, when the role of diabetes and insulin resistance began to draw attention. This review aims to provide an update on connections between insulinemia (insulin resistance) and different obesity phenotypes as well to discuss their relation to development of endometrial cancer, its clinical-morphological features and the increasing number of its molecular-biological subtypes. [ABSTRACT FROM PUBLISHER]

In the last years the treatment of type 2 diabetes mellitus (DM2) was carried out using regulators of the brain signaling systems. In DM2 the level of the brain serotonin is reduced. So far, the effect of the increase of the brain serotonin level on DM2-induced metabolic and hormonal abnormalities has been studied scarcely. The present work was undertaken with the aim of filling this gap. DM2 was induced in male rats by 150-day high-fat diet and the treatment with low dose of streptozotocin (25 mg/kg) on the 70th day of experiment. From the 90th day, diabetic rats received for two months intranasal serotonin (IS) at a daily dose of 20 μg/rat. The IS treatment of diabetic rats decreased the body weight, and improved glucose tolerance, insulin-induced glucose utilization, and lipid metabolism. Besides, it restored hormonal regulation of adenylyl cyclase (AC) activity in the hypothalamus and normalized AC stimulation by β-adrenergic agonists in the myocardium. In nondiabetic rats the same treatment induced metabolic and hormonal alterations, some of which were similar to those in DM2 but expressed to a lesser extent. In conclusion, the elevation of the brain serotonin level may be regarded as an effective approach to treat DM2 and its complications. [ABSTRACT FROM AUTHOR]

Aim: The goal of this study was to determine if the single nucleotide polymorphisms marking potential sensitivity to metformin (MF) correlate with hormone-metabolic status as well as with actual response to MF in postmenopausal cancer patients with or without Type 2 diabetes mellitus and in diabetics without cancer. Patients & methods: The carriage of ten different SNPs was evaluated in all patients by PCR, and hormone-metabolic status was estimated by anthropometry, ELISA and enzyme colorimetric assays. The response to daily 1-1.7 g of MF was studied based on hormone-metabolic parameters and indirect end points (endometrium thickness, mammographic breast density). Results & conclusion: The changes in evaluated 'antineoplastic' and metabolic response marker values were seen in 33.3 and 61.8% of the cases, respectively. Several genetic markers were found that showed an inclination to less frequent 'antineoplastic' or more frequent metabolic response to MF which may be helpful in further studies of this drug in cancer patients. [ABSTRACT FROM AUTHOR]

The idea of intrauterine or fetal factors being the cause of several prevalent noninfectious diseases in adults has recently gained the status of an axiom. One of the most thoroughly studied predictors is birth weight (BW). Although many published studies point at relations between BW and later adult morbidity or mortality, much less attention is paid to associations between baby BW and maternal morbidity. Available data suggest a sort of dichotomy in these relationships. Thus, cardiovascular risk is higher in mothers of babies with a reduced BW, while cancer risk, mainly of the breast and some other hormone-dependent cancers, is often higher among mothers of babies with a large BW (newborn macrosomia). This review addresses possible causes and endocrine mechanisms of this topic and suggests a 'particular' and 'general' solution for arising controversy. Emphasis is placed on a probable competition between chronic diseases (mainly, between female hormone-related cancer and cardiovascular pathology) within the concept of multiple causes of death. These associations should be remembered while studying the relation between offspring BW and maternal predisposition to hormone-associated cancers and other noncommunicable diseases. [ABSTRACT FROM AUTHOR]

This paper demonstrates that in breast cancer patients without overt diabetes mellitus, the antidiabetic biguanide metformin at a dose of 1500 mg/day reduces initially increased fasting insulinemia by 22.4% on average, 6 months after the onset of treatment. Since the same authors reported earlier on the association between preoperational insulinemia and breast cancer progression rate, an important conclusion from the above publication was that a Phase III randomized trial of metformin is warranted in order to assess the possible antitumor effect of this preparation. The evaluation presented below briefly addresses the history of the issue and possible targets of metformin effects beside its insulin-related action. It is argued that in selecting breast cancer patients for metformin therapy, one should take into account, along with the standard criteria, the pharmacogenetic aspects, estrogen production and specific features of estrogenic signaling, and also the expression of important metformin targets, including AMP-activated protein kinase, in tumor tissue. [ABSTRACT FROM AUTHOR]

Information related to the BRCA1 gene has increasingly become a subject for analysis by endocrinologists. For example, it is hard to dismiss the fact that, in BRCA1 mutation carriers, tumors develop predominantly in such estrogen-dependent organs as the mammary glands and ovaries but not in the endometrium. Another characteristic feature is that although BRCA1 mutants and knock-downs are unable to inhibit the transcriptional activity of estrogen receptor-a, in BRCA1 mutation carriers breast cancers are often estrogen receptor-negative and originate from the basal rather than the luminal epithelium. The latter, together with other data, suggests that BRCA1-positive breast neoplasms could be considered to be a consequence of the genotoxic variant of hormonal carcinogenesis (that is, associated with DNA damaging rather then with pure hormonal/physiological properties of hormones or their derivatives). Of indisputable significance are the data demonstrating that knocking down of the BRCA1 gene is accompanied by aromatase overexpression and the abolishment of IGF-1 receptor expression suppression, thus increasing both steroid and insulin signaling. Importantly, the endocrine-genotoxic 'liberation' found upon transfer from the wild-type to the mutant BRCA1 provides grounds to regard BRCA1 as a modulator of endocrine-genotoxic switchings (predominantly into a direction of DNA-damaging hormone effects) and also to ask whether this is a property of only this or some other tumor suppressor's. [ABSTRACT FROM AUTHOR]

The abundance of fat tissue surrounding normal and malignant epithelial mammary cells raises the questions whether such 'adipose milieu' is important in the local proinflammatory/genotoxic shift, which apparently promotes tumor development and worsens prognosis, and what conditions stimulate this shift, or 'adipogenotoxicosis.' We studied 95 mammary fat samples from 70 postmenopausal and 25 premenopausal breast cancer (BC) patients at a distance of 1.5-2.0 cm from tumors. The levels of leptin, adiponectin, TNFα and IL-6 release after 4-hr incubation of the samples were evaluated with ELISA, nitric oxide (NO) production by Griess reaction and lipid peroxidation by determination of thiobarbiturate-reactive products (TBRP). Infiltration of fat with macrophages (CD68-positive cells) and expression of cytochrome P450 1B1/estrogen 4-hydroxylase ( CYP1B1) were detected by immunohistochemistry. Aromatase ( CYP19) activity in mammary fat was measured by [ABSTRACT FROM AUTHOR]

Abstract: Factors predisposing hormone-dependent tissues to the development of tumors coincide, at least partly, with hormonal-metabolic promoters (like insulin resistance, glucose intolerance, visceral obesity, etc.) of other main non-communicable diseases. This important knowledge poses the question of whether the same approach which is applied for prevention/treatment of a metabolic syndrome and the associated endocrine disorders might also be used in preventive and therapeutic oncology. Whereas an answer to this question remains controversial and is based mainly on experimental evidence, there is accumulating clinical data suggesting a practical significance of such a strategy, even though it is not to be considered as directly cytostatic. Among the many drugs under discussion, three groups of medicines (statins, antidiabetic biguanides, and thiazolidinediones) are the most attractive. The concept of metabolic rehabilitation is proposed and used practically in an adjuvant setting for the correction of the above-mentioned endocrine-metabolic disorders commonly found in cancer patients. The current use and aim of this approach is to improve the survival of patients and limit cancer progression. Nonetheless, it also appears potentially useful as a neoadjuvant therapy as well as a prophylactic treatment earlier in life for specific groups of people with hormone-associated enhanced oncological risk. It seems possible that certain hypolipidemic and antidiabetic medicines with pleiotropic effects might be combined with traditional antisteroid prevention/therapeutic approaches in routine clinical situations as well as for overcoming resistance to standard cancer hormonal therapies including receptor-negative cases. Characteristic at the end of the 20th and at the beginning of the 21st century is an epidemic of diabetes and obesity, which might further increase the incidence of certain cancers. This makes it timely to apply hypolipidemic and antidiabetic drugs (in combination with reasonable dieting, increased physical fitness, and an in-depth knowledge of drug-gene interactions) as an approach warranting further study. [Copyright &y& Elsevier]

Excessive estrogenic influence is known to be associated with initiation/promotion of endometrial cancer (EC). Allelic polymorphisms of the genes involved in steroidogenesis/steroid metabolism may contribute to EC susceptibility. It is important to know endocrine mechanisms by which such susceptibility is acquired. Here, we compared CYP19 (aromatase) and CYP17 (17α-hydroxylase/17,20-lyase) gene polymorphisms correspondingly in 136 and 165 EC patients and in 116 and 188 non-affected women primarily of postmenopausal age. In these expanded studies we confirmed our previous observations that genotypes with longest alleles of CYP19 (A6 or A7) are over-represented (64.7±4.0 vs. 49.1±4.6%, P=0.04, and 11.0±2.7 vs. 1.7±1.2%, P=0.01)) and A2/A2 CYP17 genotype is under-represented (12.1±2.5 vs. 25.0±3.2%, P=0.001) in patients as compared to controls. Additionally, aromatase activity was studied by tritiated water release assay in tumor tissues of 32 EC patients. In carriers of A2/A2 CYP17 genotype this activity was significantly lower than in carriers of A1/A1 genotype or in combined group of A1/A1 and A1/A2 CYP17 carriers (P=0.04 in both cases). On the other side, intratumoral aromatase activity demonstrated tendency to higher values in carriers of longest CYP19 alleles (A6A6 and A6A7) than in carriers of all other CYP19 allele variants (P=0.066). Thus, specific set of genetic polymorphisms (carrying of CYP17 A1 allele and combination of longest A6 or A7 CYP19 alleles) may predispose to the induction of higher rate of local estrogen biosynthesis in malignant endometrium, that in its turn may support growth of the latter. Further studies are warranted to connect revealed regularities with the type I or II of EC. [Copyright &y& Elsevier]

Objective: To investigate the short-term hormonal and clinical effects of the aromatase inhibitor letrozole (Femara®) in patients with endometrial cancer. Materials and methods: Ten previously untreated, post-menopausal patients (mean age 59 years) with endometrial cancer, predominantly stage I disease, received letrozole 2.5 mg per day for 14 days before surgery. Clinical, sonographic, morphologic, cytologic, and hormonal-metabolic parameters (blood estradiol, follicle-stimulating hormone (FSH), luteinizing hormone (LH), glucose, and cholesterol by radioimmunoassay, enzyme immune assay, or enzyme-colorimetric methods; tumor progesterone receptors by ligand-binding assay; and aromatase activity by 3H-water release assay) were evaluated before and after treatment. Results: Treatment was well-tolerated in all patients. In two patients, pain relief in the lower part of the belly and/or decrease in intensity of uterine discharge was reported. In the three cases, substantial decreases in endometrial M-echo (ultrasound) signal were noted; the mean value of this parameter after treatment was 31.1% lower than before treatment. Blood estradiol concentration decreased by an average of 37.8% after letrozole therapy, and tumor progesterone receptor levels and aromatase activity decreased by 34.4 and 17.5%, respectively. Treatment with letrozole did not influence surgery. Conclusions: These data show that short-term treatment with letrozole in the neoadjuvant setting resulted in some positive clinical changes. Longer-term and larger-scale trials of neoadjuvant letrozole in endometrial cancer are warranted. [Copyright &y& Elsevier]

Initiation and/or promotion of endometrial cancer is known to be associated with estrogen and androgen (androstenedione) excess as well as with hyperinsulinemia/insulin resistance. It is possible that some allelic polymorphisms of the genes involved in steroidogenesis or steroid metabolism contribute to endometrial cancer susceptibility. We evaluated here the role of CYP17 biallelic (MspAI) polymorphism in 114 endometrial cancer patients compared with 182 healthy women. Our data demonstrated that A2/A2 CYP17 genotype, considered on the basis of initial breast cancer studies as ‘unfavorable’, was under-represented in endometrial cancer group (odds ratio 0.48, 95% confidence interval 0.25–0.89) that confirmed results of two other recent investigations. Carriers of this genotype were characterized by having lower blood insulin (by 120 min of oral glucose tolerance test 36.7±3.9 μU/ml vs. 90.4±16.7 μU/ml in postmenopausal women with A1/A1 genotype, P=0.04) and C-peptide levels (after night fasting 575.2±78.3 pg/ml vs. 978.9±115.7 pg/ml, respectively, P=0.04). No significant difference was found between the mean concentrations of testosterone, dehydroepiandrosterone sulfate and estradiol concentrations in patients-carriers of separate CYP17 genotypes. Thus, CYP17 polymorphism (namely, carrying the ‘normal’ A1/A1 genotype) might be one of the risk factors for endometrial cancer development. A1/A1 CYP17 variant may be associated with untraditional (non-steroidal) pathways that calls for corresponding preventive measures in high-risk groups. [Copyright &y& Elsevier]

Examines tissue-specific synthesis and oxidative metabolism of estrogens. Risk factors for developing breast cancer; Role of aromatase overexpression in the genesis of breast carcinoma; Importance of In Situ aromatase in breast tissue.

Lessons Learned: Melatonin did not increase the efficacy of systemic chemotherapy in melanoma.Metformin did not increase the efficacy of systemic chemotherapy in melanoma. Background: Current data support the possibility of antitumor activity of melatonin and metformin. Methods: From March 2014 to December 2016, 57 patients with disseminated melanoma received dacarbazine (DTIC) 1,000 mg/m2 on day 1 of a 28‐day cycle, either as monotherapy (first group) or in combination with melatonin 3 mg p.o. daily (second group) or metformin 850 mg two times a day p.o. daily (third group) as the first‐line of chemotherapy. The primary endpoint was objective response rate (ORR). Secondary endpoints were time to progression (TTP), overall survival (OS), immunologic biomarkers, and quality of life. Results: ORR was 7% and did not differ among the treatment groups. Median TTP was 57, 57, and 47 days, respectively, in the first, second, and third groups (р =.362). Median OS was 236, 422, and 419 days, respectively (p =.712). Two patients from the combinations groups showed delayed response to therapy. The increase of CD3+CD4+HLA‐DR+ lymphocytes (p =.003), CD3+CD8+HLA‐DR+ (p =.045), CD3+CD8+ lymphocytes (p =.012), CD4+CD25highCD127low lymphocytes (p =.029), and overall quantity of lymphocytes (p =.021) was observed in patients with clinical benefit. Conclusion: No benefit was found in either combination over DTIC monotherapy. Delayed responses in melatonin and metformin combination groups were registered. The increase of lymphocyte subpopulations responsible for antitumor immune response demonstrates the immune system's potential involvement in clinical activity. [ABSTRACT FROM AUTHOR]

The phenomenon of the primary or acquired resistance of cancer cells to antitumor drugs is among the key problems of oncology. For breast cancer, the phenomenon of the resistance to hormonal or target therapy may be based on the numerous mechanisms including the loss or mutation of estrogen receptor, alterations of antiapoptotic pathways, overexpression of growth-related signaling proteins, etc. The perspective approaches for overcoming the resistance may be based on the usage of compounds such as inhibitors of the cell energetic metabolism. Among the latter, the antidiabetic drug metformin exerts antitumor activity via the activation of AMPK and the subsequent inhibition of mTOR signaling. The experiments were performed on the ERα-positive MCF-7 breast cancer cells, the MCF-7 sublines resistant to tamoxifen (MCF-7/T) and rapamycin (MCF-7/Rap), and on triple-negative MDA-MB-231 breast cancer cells. We have demonstrated metformin's ability to enhance the cytostatic activity of the tamoxifen and rapamycin on both parent MCF-7 cells and MCF-7-resistant derivates mediated via the suppression of mTOR signaling and growth-related transcriptional factors. The cooperative effect of metformin and tested drugs was realized in an estrogen-independent manner, and, in the case of tamoxifen, was associated with the activation of apoptotic cell death. Similarly, the stimulation of apoptosis under metformin/tamoxifen co-treatment was shown to occur in the MCF-7 cells after steroid depletion as well as in the ERα-negative MDA-MB-231 cells. We conclude that metformin co-treatment may be used for the increase and partial restoration of the cancer cell sensitivity to hormonal and target drugs. Moreover, the combination of metformin with tamoxifen induces the apoptotic death in the ERα-negative breast cancer cells opening the additional perspectives in the treatment of estrogen-independent breast tumors. [ABSTRACT FROM AUTHOR]

The involvement of estrogens, which influence many physiologic processes, has been shown in the development or progression of several diseases including some cancers, most notably breast cancer, and autoimmune disorders. Estrogenic signal is transferred via estrogen receptors (ER) which have dual localization, predominantly intracellular but also in plasma membrane. The discovery of membrane-associated ER (mER) has greatly expanded our understanding of estrogen action; upon ligand binding, mER rapidly activate different signaling pathways inducing downstream transcription factors. Some target genes of the mER pathway may be activated independently of the intracellular ER. Additionally, intracellular ER action can be modulated by mER-initiated signaling. Most notably, the identification of autoantibodies reacting with ER (ERAB) and their possible pathogenic role in autoimmunity and cancer have opened a new path for the research in the estrogen-related receptor activity. In this review, we briefly recapitulate the localization and function of ER and mostly discuss the possible role of ERAB as novel potential prognostic and/or predictive tools in autoimmunity and cancer. [ABSTRACT FROM AUTHOR]

mTOR inhibitors are considered today to be one of the most promising anticancer drugs. Here to study the mechanism of the acquired resistance of MCF-7 breast cancer cells to mTOR inhibitors two different models of the cell resistance were used: rapamycin-resistant MCF-7/Rap subline developed under long-term rapamycin treatment, and metformin-resistant MCF-7/M subline obtained by long-term metformin treatment. We have found that both resistant sublines were characterized by common features: increased expression of mTOR-interacting Raptor protein, increased phosphorylation of Akt, and activation of growth-related transcriptional factor AP-1. Cell response to mTOR inhibitors was partially restored under treatment with PI3K inhibitor wortmannin supporting the direct connection between Akt activation and poor cell response to therapeutic drugs. Transfection of mir-181c, one of the positive regulators of Akt and mTOR, led to an increase in the cell resistance to both mTOR inhibitors, rapamycin and metformin, which correlated with Raptor overexpression and activation of Akt/AP-1 signaling. In general, the effect of Raptor overexpression in the resistant cells, as well as the ability of mir-181c to modulate the Raptor expression, can open novel perspectives in the treatment of rapalogues-resistant cancers, based on the drugs design targeting mir-181c/Raptor axis. • Novel cell sublines with resistance to mTOR inhibitors were developed. • Activation of mTOR-interacting Raptor protein, Akt, and AP-1 factor are associated with resistance. • Wortmannin restores cell sensitivity to mTOR inhibitors. • mir-181c is involved in the cell resistance to mTOR inhibitors. [ABSTRACT FROM AUTHOR]