Targeting MUC1-C inhibits the AKT-S6K1-elF4A pathway regulating TIGAR translation in colorectal cancer.

BACKGROUND: Colorectal cancer is third most common malignancy and is the second most common cause of cancer-related death. The MUC1 heterodimeric protein is aberrantly overexpressed in colorectal cancer and has been linked to poor outcomes in this disease. Here, we investigate the effects of the MUC1-C subunit inhibitor (GO-203), which disrupts MUC1-C homo-oligomerization, on human colorectal cancer cells. METHODS: TIGAR mRNA level was determined using qRT-PCR. Western blotting was used to measure TIGAR protein level and AKT-mTOR-S6K1 pathways. Reactive oxygen species and apoptosis were measured by flow cytometry. Effect of MUC1-C peptide, GO-203 was studied on colorectal xenograft tumors. Immunohistochemistry was utilized for TIGAR staining. RESULTS: Treatment of MUC1-overexpressing SKCO-1 and Colo-205 colon cancer cells with GO-203 was associated with downregulation of the TP53-inducible glycolysis and apoptosis regulator (TIGAR) protein. TIGAR promotes the shunting of glycolytic intermediates into the pentose phosphate pathway and thus is of importance for maintaining redox balance. We show that GO-203-induced suppression of TIGAR is mediated by inhibition of AKT and the downstream mTOR pathway. The results also demonstrate that targeting MUC1-C blocks eIF4A cap-dependent translation of TIGAR. In concert with these results, GO-203-induced suppression of TIGAR was associated with decreases in GSH levels. GO-203 treatment also resulted in increases in reactive oxygen species (ROS) and loss of mitochondrial transmembrane potential. Consistent with these results, GO-203 inhibited the growth of colon cancer cells in vitro and as xenografts in nude mice. Inhibition of MUC1-C also downregulated TIGAR expression in xenograft tissues. CONCLUSIONS: These findings indicate that MUC1-C is a potential target for the treatment of colorectal cancer. Colorectal cancer patients who overexpress MUC1-C may be candidates for treatment with the MUC1-C inhibitor alone or in combination therapy with other agents.

Isolated cervical lymph node metastasis of renal pelvic squamous cell carcinoma: A case report.

A 78-year-old man was admitted to the Department of Otolaryngology of our hospital with bilateral lymph node swelling of the neck. Pathological examination revealed squamous cell carcinoma (SCC). He underwent computed tomography (CT) of the neck and chest, upper gastrointestinal endoscopy and laryngoscopy to locate a primary tumour, however, no obvious tumour was detected. Eight months later, a renal tumour without regional lymph node swelling was found when a chest CT scan was performed again. We then performed a right nephroureterectomy and regional lymphadenectomy. Pathological examination revealed SCC of the renal pelvis, pT3, grade 3, without regional lymph node metastasis. This pathological finding for the kidney was virtually the same as that for cervical lymph nodes. Therefore, it was thought that his cervical tumours had metastasized from the renal pelvic SCC. To the best of our knowledge, there are no reports of renal pelvic carcinoma without regional lymph node metastasis having only cervical lymph node metastasis. This is the first case of isolated cervical lymph node metastasis from renal pelvic SCC.

Disappearance of a major thrombus in the brachiocephalic vein without anticoagulant therapy in a patient with seminoma: A case report.

This is the first case report describing brachiocephalic vein thrombosis without compression by a metastatic tumour during chemotherapy for testicular cancer. According to previous reports of testicular cancer patients with a major thrombus, anticoagulant therapy was required to resolve all cases. However, in the present case, a major thrombus in the brachiocephalic vein disappeared without anticoagulant therapy. This 42-year-old man was diagnosed with testicular seminoma and multiple metastases to the para-aortic lymph nodes. After 3 cycles of cisplatin, etoposide and bleomycin (PEB) therapy, a major thrombus in the right brachiocephalic vein was recognized on a computed tomography (CT) scan. Although no anticoagulant therapy was undertaken, the thrombus in the right brachiocephalic vein was no longer visible on CT after the fourth cycle of PEB therapy.

Inhibition of the MUC1-C oncoprotein is synergistic with cytotoxic agents in the treatment of breast cancer cells.

Mucin 1 (MUC1) is a heterodimeric glycoprotein that is aberrantly overexpressed in most human breast cancers. The oncogenic MUC1-C subunit promotes survival and blocks the apoptotic response to genotoxic anticancer agents. In the present studies, human MCF-7 and ZR-75-1 breast cancer cells were treated with the MUC1-C inhibitor, GO-203, a cell-penetrating peptide that blocks MUC1-C homodimerization and thereby its oncogenic function. Treatment with GO-203 was found to promote the apoptotic response of MCF-7 and ZR-75-1 cells to the therapeutic drugs taxol and doxorubicin (DOX). This effect was (1) attenuated by a pan-caspase inhibitor, and (2) mediated, at least in part, by activation of the effector caspase-7 and cleavage of the downstream substrate PARP. Further analysis of the interaction between GO-203 and taxol using isobolograms, which evaluate the nature of the interaction of two drugs, demonstrated that the combination is highly synergistic. These results were supported by combination index (CI) analysis with values of less than 1. GO-203 was also highly synergistic with DOX in studies of both MCF-7 and ZR-75-1 breast cancer cells. These findings indicate that blocking MUC1-C function could be effective in combination with taxol and DOX for the treatment of breast cancer.

MUC1-C oncoprotein regulates glycolysis and pyruvate kinase M2 activity in cancer cells.

Aerobic glycolysis in cancer cells is regulated by multiple effectors that include Akt and pyruvate kinase M2 (PKM2). Mucin 1 (MUC1) is a heterodimeric glycoprotein that is aberrantly overexpressed by human breast and other carcinomas. Here we show that transformation of rat fibroblasts by the oncogenic MUC1-C subunit is associated with Akt-mediated increases in glucose uptake and lactate production, consistent with the stimulation of glycolysis. The results also demonstrate that the MUC1-C cytoplasmic domain binds directly to PKM2 at the B- and C-domains. Interaction between the MUC1-C cytoplasmic domain Cys-3 and the PKM2 C-domain Cys-474 was found to stimulate PKM2 activity. Conversely, epidermal growth factor receptor (EGFR)-mediated phosphorylation of the MUC1-C cytoplasmic domain on Tyr-46 conferred binding to PKM2 Lys-433 and inhibited PKM2 activity. In human breast cancer cells, silencing MUC1-C was associated with decreases in glucose uptake and lactate production, confirming involvement of MUC1-C in the regulation of glycolysis. In addition, EGFR-mediated phosphorylation of MUC1-C in breast cancer cells was associated with decreases in PKM2 activity. These findings indicate that the MUC1-C subunit regulates glycolysis and that this response is conferred in part by PKM2. Thus, the overexpression of MUC1-C oncoprotein in diverse human carcinomas could be of importance to the Warburg effect of aerobic glycolysis.

Successful management of metastatic urothelial carcinoma with gemcitabine and Paclitaxel chemotherapy in a hemodialysis patient.

This is the first report of urothelial carcinoma (UC) in a hemodialysis (HD) patient treated with almost the same doses of gemcitabine and paclitaxel (GP) as those administered to patients with normal renal function. There have been some reports of UC treated with cisplatin-based chemotherapy in HD patients. However, there have only been a few reports of UC treated with GP in HD patients. Furthermore, to our knowledge, there has not been any report of UC in a HD patient treated with almost the same doses of GP as those in patients with normal renal function. Following cystectomy for bladder cancer, a 73-year-old woman undergoing HD developed lung metastasis and received combination chemotherapy with almost the same doses of GP as those in patients with normal renal function. After three cycles were completed, metastatic tumors disappeared and there has not been any recurrence or metastasis for 1 year to date. Furthermore, there were no grade 3 or 4 adverse effects during this treatment.

Thrombosis in inferior vena cava due to enlarged renal cysts in autosomal dominant polycystic kidney disease.

We report a rare case of thrombosis in the inferior vena cava (IVC) due to enlarged cysts in autosomal dominant polycystic kidney disease. A 71-year-old woman visited our hospital with a complaint of rapid left lower extremity swelling. Computed tomography (CT) revealed massive thrombosis from the IVC to the bilateral common iliac vein. The extrinsic mechanical stress of renal cysts to the IVC seemed to have induced thrombosis in the vein that resulted in the cause of severe edema in the left lower extremity. Her renal cysts were percutaneously punctured for the relief of compression and she received injection of 99.5% ethanol for prevention against reaccumulation of cyst fluid after IVC filter had been positioned. The edema of her left lower extremity improved temporarily, however, follow-up CT two months after cyst puncture showed reaccumulation of the fluid. Therefore, excision of the responsible cyst wall by open surgery was carried out.

Vitamin E succinate induced apoptosis and enhanced chemosensitivity to paclitaxel in human bladder cancer cells in vitro and in vivo.

There have been several studies on the antitumor activities of vitamin E succinate (alpha-TOS) as complementary and alternative medicine. In the present study, we investigated the cytotoxic effect of alpha-TOS and the enhancement of chemosensitivity to paclitaxel by alpha-TOS in bladder cancer. KU-19-19 and 5637 bladder cancer cell lines were cultured in alpha-TOS and/or paclitaxel in vitro. Cell viability, flow cytometric analysis, and nuclear factor-kappa B (NF-kappaB) activity were analyzed. For in vivo therapeutic experiments, pre-established KU-19-19 tumors were treated with alpha-TOS and/or paclitaxel. In KU-19-19 and 5637 cells, the combination treatment resulted in a significantly higher level of growth inhibition, and apoptosis was significantly induced by the combination treatment. NF-kappaB was activated by paclitaxel; however, the activation of NF-kappaB was inhibited by alpha-TOS. Also, the combination treatment significantly inhibited tumor growth in mice. In the immunostaining of the tumors, apoptosis was induced and proliferation was inhibited by the combination treatment. Combination treatment of alpha-TOS and paclitaxel showed promising anticancer effects in terms of inhibiting bladder cancer cell growth and viability in vitro and in vivo. One of the potential mechanisms by which the combination therapy has synergistic cytotoxic effects against bladder cancer may be that alpha-TOS inhibits NF-kappaB induced by chemotherapeutic agents.

[Two cases of urinary retention secondary to benign inflammatory nervous diseases].

We report two cases of acute urinary retention secondary to benign inflammatory nervous disease. Case 1 is in a 48-year-old male who was diagnosed with aseptic meningitis. Case 2 is in a 67-year-old male who was diagnosed with acute disseminated encephalomyelitis. These two cases differred in specific mechanism of the disease, but both shared symptoms of temporal voiding disturbance due to sacral radiculopathy (Elsberg syndrome). This condition is extremely rare, but should be kept in mind because delayed treatment can lead to permanent impairment.

Vesical endometriosis following the menopause.

We report a rare case of vesical endometriosis in a 65-year-old postmenopausal woman. An abdominal hysterectomy had been performed 34 years previously, and exogenous estrogens had not been administered. The hormone levels were normal for a castrated female subject. The patient was treated surgically with transurethral resection and the following hormonal therapy. Endometriosis of the urinary tract can happen even in postmenopausal women.

Renal damage inhibited in mice lacking angiotensinogen gene subjected to unilateral ureteral obstruction.

OBJECTIVES: To determine how angiotensin II (Ang II) contributes to renal interstitial fibrosis, the inflammatory response, and tubular cell apoptosis and proliferation in unilateral ureteral obstruction using mice genetically deficient in angiotensinogen (Agt(-/-)). METHODS: The left kidney of wild-type mice (WT; C57BL/6) and Agt(-/-) mice was obstructed for 2 weeks, and then both kidneys were harvested. The serum Ang II levels were determined by radioimmunoassay. The expression of transforming growth factor-beta in renal tissue was assessed using enzyme-linked immunosorbent assay. The renal tissue was stained with Masson's trichrome. Renal tubular proliferation and apoptosis was detected by immunostaining for proliferating cell nuclear antigen and single-stranded DNA, respectively. Interstitial leukocyte and macrophage infiltration was investigated by immunostaining for CD45 and F4/80, respectively. RESULTS: The serum Ang II levels in the Agt(-/-) mice were significantly lower than those in the WT mice (P < .01), and tissue transforming growth factor-beta in the obstructed kidney of Agt(-/-) mice was significantly lower than that in WT mice (P < .05). Interstitial collagen deposition was significantly lower in the Agt(-/-) obstructed kidneys than in the WT obstructed kidneys (P < .01). Tubular proliferation was significantly greater and tubular apoptosis was significantly lower in the Agt(-/-) obstructed kidneys than in the WT obstructed kidneys (P < .01 and P < .01, respectively). Interstitial infiltration by leukocytes and macrophages was significantly lower in the Agt(-/-) obstructed kidneys than in the WT obstructed kidneys (P < .01 and P < .01, respectively). CONCLUSIONS: The results of the present study support the targeting of Ang II as a reasonable approach by which to prevent renal tissue damage in unilateral ureteral obstruction.

[Metastatic malignant melanoma of the urinary bladder presenting with hematuria: a case report].

A 65-year-old man complained of macroscopic hematuria and urinary obstruction. A blood clot in the bladder eliminated transurethrally demonstrated a solitary tumor at the dome of the bladder. Transurethral resection of the bladder tumor (TUR-Bt) was performed, and histological diagnosis was malignant melanoma. Physical examination revealed a black-pigmented site on the lateral border of the right foot sole, which was dermatologically diagnosed as malignant melanoma. The vesical site was diagnosed as a metastatic melanoma of the bladder. Metastatic neoplasms of the bladder are rare, ranging from 0.1 to 6.2 percent of all bladder tumors. To our knowledge, approximately forty percent of metastatic neoplasms of the bladder originate from melanoma. Therefore, an atypical nodular lesion encountered during cystoscopy may be metastasis of malignant melanoma and dermatic lesions should be investigated.