BackgroundProstate cancer is one of the most commonly diagnosed cancers in men worldwide. Currently available therapies for metastatic prostate cancer are only marginally effective. Therefore, new therapeutic agents are urgently needed to improve patient outcome. Isoalantolactone (IATL), an active sesquiterpene naturally present in many vegetables and medicinal plants, is known to induce cell death and apoptosis in various cancer cell lines. Nevertheless, antitumor mechanisms initiated by IATL in cancer cells have not been fully defined.MethodsCell apoptosis and cellular ROS levels were analyzed by flow cytometry. Western blot and qRT-PCR were used to analyze the protein and mRNA levels of indicated molecules, respectively. Nude mice xenograft model was used to test the effects of IATL on prostate cancer cell growth in vivo.ResultsIn this study, we found that IATL dose-dependently inhibited cancer cell growth and induced apoptosis in PC-3 and DU145 cells. Mechanistically, our data found that IATL induced reactive oxygen species (ROS) production, resulting in the activation of endoplasmic reticulum stress pathway and eventually cell apoptosis in prostate cancer cells. IATL also decreased the protein expression levels of p-STAT3 and STAT3, and the effects of IATL were reversed by pretreatment with N-acetyl-L-cysteine (NAC). In vivo, we found that IATL inhibited the growth of prostate cancer xenografts without exhibiting toxicity. Treatment of mice bearing human prostate cancer xenografts with IATL was also associated with induction of ER stress and inhibtion of STAT3.ConclusionIn summary, our results unveil a previously unrecognized mechanism underlying the biological activity of IATL, and provide a novel anti-cancer candidate for the treatment of prostate cancer.

Background/Aims: Melanoma antigen A6 (MAGEA6) is a cancer-specific ubiquitin ligase of AMP-activated protein kinase (AMPK). The current study tested MAGEA6 expression and potential function in renal cell carcinoma (RCC). Methods: MAGEA6 and AMPK expression in human RCC tissues and RCC cells were tested by Western blotting assay and qRT-PCR assay. shRNA method was applied to knockdown MAGEA6 in human RCC cells. Cell survival and proliferation were tested by MTT assay and BrdU ELISA assay, respectively. Cell apoptosis was tested by the TUNEL assay and single strand DNA ELISA assay. The 786-O xenograft in nude mouse model was established to test RCC cell growth in vivo. Results: MAGEA6 is specifically expressed in RCC tissues as well as in the established (786-O and A498) and primary human RCC cells. MAGEA6 expression is correlated with AMPKα1 downregulation in RCC tissues and cells. It is not detected in normal renal tissues nor in the HK-2 renal epithelial cells. MAGEA6 knockdown by targeted-shRNA induced AMPK stabilization and activation, which led to mTOR complex 1 (mTORC1) in-activation and RCC cell death/apoptosis. AMPK inhibition, by AMPKα1 shRNA or the dominant negative AMPKα1 (T172A), almost reversed MAGEA6 knockdown-induced RCC cell apoptosis. Conversely, expression of the constitutive-active AMPKα1 (T172D) mimicked the actions by MAGEA6 shRNA. In vivo, MAGEA6 shRNA-bearing 786-O tumors grew significantly slower in nude mice than the control tumors. AMPKα1 stabilization and activation as well as mTORC1 in-activation were detected in MAGEA6 shRNA tumor tissues. Conclusion: MAGEA6 knockdown inhibits human RCC cells via activating AMPK signaling.

Abstract. Metastatic renal cell carcinoma (RCC) disseminates to a number of organ sites and few patients demonstrate long-term survival following surgery. However, synchronous metastasis of RCC to the contralateral adrenal gland and pancreas is rare. In the present report, a case of synchronous RCC metastasis to the contralateral adrenal gland and pancreas in a 55-year-old patient, with an 116x92x61 mm right renal tumor and a 96x79x57 mm left adrenal lesion, is described. In April 2007, right nephrectomy was performed to treat the RCC, left adrenalectomy was performed to treat the adrenal tumor and the pancreatic metastases were resected. The patient remained alive at the 7-year follow-up appointment. IntroductionNumerous patients with RCC remain asymptomatic until the late stages of the disease. The prevalence of the classic triad of flank pain, gross haematuria and a palpable abdominal mass is rare, while paraneoplastic syndromes occur in ~30% of patients with symptomatic RCCs. A small number of patients present with symptoms caused by metastatic RCC (1). Metastatic disease at diagnosis is observed in ~25-30% of patients with renal cell carcinoma (RCC), and <5% of patients exhibit solitary metastasis. The most common distant RCC metastasis sites are the lungs (50-60%), bone (30-40%), liver (30-40%) and brain (5%); however, metastasis may involve virtually any organ site (2). While adrenal metastasis from RCC to the ipsilateral adrenal gland is common, synchronous metastasis of RCC to the contralateral adrenal gland is rare, and affects only 0.51% of patients (6/1,179) (3). Pancreatic metastases from RCC are additionally rare (accounting for 1.5-3% of all metastatic RCC cases), and these cases typically present a number of years subsequent to the primary RCC diagnosis (4,5).For localised RCC, surgery is the only curative treatment with high-quality evidence and for metastatic RCC surgery is curative only if the total tumor burden can be removed (1). As prognosis is directly associated with the stage or degree of tumor dissemination, metastatic RCC generally equates to a poor prognosis for patients; indeed, response rates for treated patients remain low, at ~15-25%, with 5-year survival rates of 5-10% and overall median survival of <1 year (2). However, in certain cases, radical resection of metastases may prolong survival. In the present paper, a case of synchronous RCC metastasis to the contralateral adrenal gland and pancreas is reported. The patient remained alive at the final follow-up appointment, a total of 7 years subsequent to undergoing simultaneous right nephrectomy, left adrenalectomy and segmental pancreatectomy. Case reportA 55-year-old man with no relevant medical history visited the Transplantation Center of The First Affiliated Hospital at Wenzhou Medical University (Wenzhou, China) to undergo a routine physical examination in March 2007. Abdominal magnetic resonance imaging (MRI; 1.5T; GE Healthcare, Little Chalfont, UK) revealed a 99x81 mm right renal tumor and a 94x72 mm left adrenal lesion (...

Chemo-immunotherapy is a promising model for combination treatment of cancer. Many solid tumors overexpress programmed cell death ligand (PD-L1) for immune suppression. In this study, a PD-L1 binding peptide conjugate...

A peptide/DNA nanocomplex was developed to targeted delivering chemotherapeutics and photosensitizer to cancer cells for efficient combination therapy. Chemotherapeutic drug doxorubicin (DOX) and photosensitizer 5, 10, 15, 20-tetra (1-methylpyridine-4-yl) porphyrin...

Sustained activation of PI3K-Akt-mTOR cascade is important for renal cell carcinoma (RCC) cell progression. GNE-477 is a novel and efficacious PI3K-mTOR dual inhibitor. The current study tested its anti-RCC cell activity. In the primary cultured human RCC cells, GNE-477 potently inhibited cell growth, viability and proliferation, as well as cell cycle progression, migration and invasion. Furthermore, it induced robust apoptosis activation in primary RCC cells, but being non-cytotoxic to HK-2 epithelial cells and primary human renal epithelial cells. In the primary RCC cells GNE-477 inactivated PI3K-Akt-mTOR cascade by blocking phosphorylation of p85, Akt1, p70S6K1 and S6. Restoring Akt-mTOR activation by a constitutively-active Akt1 reversed GNE-477-induced anti-RCC cell activity. In nude mice intraperitoneal injection of GNE-477 potently suppressed RCC xenograft tumor growth. Collectively, targeting PI3K-Akt-mTOR cascade by GNE-477 inhibits RCC cell growth in vitro and in vivo.

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Androgen receptor (AR) is an androgen-activated transcription factor of the nuclear receptor superfamily. AR plays a role in the development and progression of prostate cancer (PCa). However, the exact role of AR in PCa metastasis remains unclear. In the present study, we aimed to elucidate the function of AR in PCa. We found that eukaryotic translation initiation factor (EIF) 5A2, an elongation factor that induces epithelial-to-mesenchymal transition (EMT) in PCa cells, was significantly upregulated after 5α-dihydrotestosterone (DHT) stimulation and downregulated after anti‐androgen bicalutamide treatment in PCa cells with high AR expression, but not in cells with low AR expression. Moreover, eIF5A2 knockdown could eliminate DHT-induced invasion and migration of AR-positive PCa cells. DHT treatment decreased epithelial expression of E‐cadherin and β-catenin but increased the expression of the mesenchymal marker proteins Vimentin and N-cadherin. DHT therefore induced EMT, and knockdown of eIF5A2 inhibited DHT-induced EMT. Moreover, in vivo study, Luciferase signals from the lungs of the eIF5A2 plasmid group indicated higher metastasis ability, and the eIF5A2 siRNA group had lower metastasis ability. Our results suggest that AR positively regulates eIF5A2 expression in androgen-dependent cells, and stimulation of AR expression and signaling in prostate tumors promotes PCa metastasis by EMT induction and upregulation of eIF5A2.