The LAT1 inhibitor JPH203 suppresses the growth of castration-resistant prostate cancer through a CD24-mediated mechanism.

L-type amino acid transporter 1 (LAT1) is specifically expressed in many malignancies, contributes to the transport of essential amino acids, such as leucine, and regulates the mammalian target of rapamycin (mTOR) signaling pathway. We investigated the expression profile and functional role of LAT1 in prostate cancer using JPH203, a specific inhibitor of LAT1. LAT1 was highly expressed in castration-resistant prostate cancer (CRPC) cells, including C4-2 and PC-3 cells, but its expression level was low in castration-sensitive LNCaP cells. JPH203 significantly inhibited [14C] leucine uptake in CRPC cells but had no effect in LNCaP cells. JPH203 inhibited the proliferation, migration, and invasion of CRPC cells but not of LNCaP cells. In C4-2 cells, Cluster of differentiation (CD) 24 was identified by RNA sequencing as a novel downstream target of JPH203. CD24 was downregulated in a JPH203 concentration-dependent manner and suppressed activation of the Wnt/ß-catenin signaling pathway. Furthermore, an in vivo study showed that JPH203 inhibited the proliferation of C4-2 cells in a castration environment. The results of this study indicate that JPH203 may exert its antitumor effect in CRPC cells via mTOR and CD24.

Functional analysis of LAT3 in prostate cancer: Its downstream target and relationship with androgen receptor.

L-type amino acid transporter 3 (LAT3, SLC43A1) is abundantly expressed in prostate cancer (PC) and is thought to play an essential role in PC progression through the cellular uptake of essential amino acids. Here, we analyzed the expression, function, and downstream target of LAT3 in PC. LAT3 was highly expressed in PC cells expressing androgen receptor (AR), and its expression was increased by dihydrotestosterone treatment and decreased by bicalutamide treatment. In chromatin immunoprecipitation sequencing of AR, binding of AR to the SLC43A1 region was increased by dihydrotestosterone stimulation. Knockdown of LAT3 inhibited cell proliferation, migration, and invasion, and the phosphorylation of p70S6K and 4EBP-1. Separase (ESPL1) was identified as a downstream target of LAT3 by RNA sequencing analysis. In addition, immunostaining of prostatectomy specimens was performed. In the multivariate analysis, high expression of LAT3 was an independent prognostic factor for recurrence-free survival (hazard ratio: 3.24; P = .0018). High LAT3 expression was correlated with the pathological T stage and a high International Society of Urological Pathology grade. In summary, our results suggest that LAT3 plays an important role in the progression of PC.

Higher serum testosterone levels predict poor prognosis in castration-resistant prostate cancer patients treated with docetaxel.

BACKGROUND: The role of testosterone as a prognostic factor for castration-resistant prostate cancer treated with docetaxel in Japan was investigated. METHODS: A total of 164 patients with castration-resistant prostate cancer who received docetaxel treatment at Chiba University Hospital and an affiliated hospital were retrospectively analyzed. Testosterone and other clinical factors at the start of docetaxel treatment were evaluated with respect to overall survival and progression-free survival. RESULTS: Of the 164 patients, 69 had high-volume tumors. The median prostatic-specific antigen was 27.0 ng/mL. The median testosterone was 13.0 ng/dL. The rates of bone and visceral metastases were 80.1% and 8.8%, respectively. For progression-free survival, testosterone ≥13 ng/dL was an independent prognostic factor only on univariate analysis (hazard ratio, 1.81; P = .0108). For overall survival, testosterone ≥ 1.3 ng/dL (hazard ratio, 3.37; P < .0001), high volume (hazard ratio, 3.06; P = .0009), and prostate-specific antigen ≥ 27.0 ng/mL (hazard ratio, 2.75; P = .0013) were independent prognostic factors on multivariate analysis. When assessing related clinical factors, higher serum testosterone was associated with visceral metastasis, high volume, and prostate-specific antigen. Based on three prognostic factors (testosterone, high volume, prostate-specific antigen), a risk classification was developed. The high-risk group (3 risk factors) showed a significantly shorter overall survival compared to the moderate-risk (2 risk factors) and low-risk (0-1 risk factor) groups (P < .0001). CONCLUSIONS: The present study identified higher serum testosterone (≥13 ng/dL) as a significant prognostic factor in castration-resistant prostate cancer patients treated with docetaxel therapy.

Nadir Testosterone after Long-Term Followup Predicts Prognosis in Patients with Prostate Cancer Treated with Combined Androgen Blockade.

PURPOSE: We examined the clinical significance of long-term serum testosterone monitoring to predict the prognosis of patients with prostate cancer treated with combined androgen blockade. MATERIALS AND METHODS: We retrospectively analyzed the records of 225 patients who underwent combined androgen blockade as first line therapy for prostate cancer. The prognostic values of testosterone and other clinical factors were evaluated with respect to prostate specific antigen progression-free and overall survival. RESULTS: Median patient age was 73.0 years, median prostate specific antigen was 42.6 ng/ml and median followup was 45.8 months. No variable associated with testosterone was predictive of progression-free survival. With regard to overall survival on univariate analysis nadir testosterone less than 16 ng/dl (p = 0.0190), less than 20 ng/dl (p = 0.0020) and less than 32 ng/dl (p = 0.0146) were significant together with other clinical factors. In contrast, nadir testosterone less than 8 and less than 12 ng/dl were not significant. Multivariate analysis showed that nadir testosterone less than 20 ng/dl was the significant prognostic factor (p = 0.0048). In addition, time to nadir testosterone was about 1 year (11.3 months). Patients were divided into rapid and slow types based on time to testosterone less than 20 ng/dl before and after 6 months, respectively. No significant difference in overall survival was observed between the 2 types. The current results suggest that the critical factor for prognosis was not a rapid decrease but whether nadir testosterone achieved a level of less than 20 ng/dl. CONCLUSIONS: Nadir testosterone 20 ng/dl was the most significant cutoff level for overall survival in Japanese patients with prostate cancer treated with combined androgen blockade.

Association Between Residual Urine Volume and Recurrence Among Patients at High Risk of Non-Muscle-Invasive Bladder Carcinoma With Versus Without Bacillus Calmette-Guérin Treatment.

Non-muscle-invasive bladder carcinoma often occurs in older adults, who often also have urinary dysfunction. The residual urine volume is an important indicator of urinary dysfunction. However, the impact of the residual urine volume on intravesical recurrence remains unclear. In the present study, we analyzed the data of 372 patients at high or very high risk of cancer progression according to the Japanese Urological Association classification who had undergone transurethral resection of a bladder tumor. In univariate analysis, postoperative absence of intravesical Bacillus Calmette-Guérin (BCG) induction was an independent risk factor for intravesical recurrence (hazard ratio 1.94, absence versus presence, p = 0.0019). The incidence of intravesical recurrence did not significantly differ between the mild, intermediate, and severe residual urine groups in the total cohort. Among the BCG-treated cohort, the three groups showed similar trends. Among the non-BCG-treated cohort, although the patients with more than 100 ml of residual urine tended to have more intravesical recurrence than patients with a smaller residual urine volume, this difference did not reach statistical significance. BCG treatment is recommended for patients at high risk of bladder carcinoma. Patients with a large residual urine volume without BCG treatment may be at high risk of intravesical recurrence.

Copy Number Gain in Androgen Receptors Predicts the Poor Prognosis in Japanese Castration-resistant Prostate Cancer.

BACKGROUND/AIM: The prognostic significance of androgen receptor amplification (AR amp) in cell-free DNA (cfDNA) was studied in Japanese patients with castration-resistant prostate cancer (CRPC). PATIENTS AND METHODS: A total of 120 serum samples were obtained from 38 patients with CRPC. Serum cfDNA was purified and the AR copy number was determined. Factors associated with progression-free survival (PFS) and overall survival (OS) were statistically investigated. RESULTS: The number of patients administered enzalutamide (Enza)/abiraterone (Abi)/docetaxel (DTX) was 33/25/11, respectively. The median PSA was 16.5 ng/ml. Thirty patients (79%) had bone metastases and three patients (7.9%) had lung metastases. The median follow-up was 655 days. The median initial AR copy number was 1.27 (1.10-11.50); an AR copy number of 1.27 or higher was defined as an AR-amp. Regarding PFS, the presence of AR-amp, Gleason score (GS), and ALP were significant factors in univariate analysis. In multivariate analysis, AR amplification was an independent prognostic factor (hazard ratio=7.7, p=0.0035). For OS, PSA and AR-amp were significant factors. In multivariate analysis, AR-amp (hazard ratio=4.65, p=0.0188) was the only independent prognostic factor. CONCLUSION: AR-amp was associated with high nadir PSA and low iPSA/PSA ratio. AR-amp was significantly associated with poor prognosis in Japanese patients with CRPC.

Image sensor pixel with on-chip high extinction ratio polarizer based on 65-nm standard CMOS technology.

In this study, we demonstrate a polarization sensitive pixel for a complementary metal-oxide-semiconductor (CMOS) image sensor based on 65-nm standard CMOS technology. Using such a deep-submicron CMOS technology, it is possible to design fine metal patterns smaller than the wavelengths of visible light by using a metal wire layer. We designed and fabricated a metal wire grid polarizer on a 20 × 20 µm(2) pixel for image sensor. An extinction ratio of 19.7 dB was observed at a wavelength 750 nm.

Prognostic Value of High-Sensitivity Modified Glasgow Prognostic Score in Castration-Resistant Prostate Cancer Patients Who Received Docetaxel.

The Glasgow prognostic score, a marker of systemic inflammation, is associated with clinical outcomes in different cancers including prostate cancer. However, there is no evidence for the relationship between the high-sensitivity modified Glasgow prognostic score (Hs-mGPS) in prostate cancer and its prognosis. This study aimed to investigate the prognostic significance of Hs-mGPS in castration-resistant prostate cancer (CRPC) treated with docetaxel. We retrospectively analyzed clinical datasets from 131 CRPC patients who received docetaxel treatment at Chiba University Hospital and a related hospital. Clinical factors including Hs-mGPS before docetaxel treatment were evaluated according to overall survival. The numbers of patients with Hs-mGPS of 0, 1, and 2 were 88, 30, and 13, respectively. The median prostate-specific antigen (PSA) level was 28.9 ng/mL. The median testosterone level was 13.0 ng/dL. The percentages of bone and visceral metastases were 80.8% and 10.2%, respectively. For overall survival, Hs-mGPS ≥ 1 (hazard ratio of 2.41; p = 0.0048), testosterone ≥ 13.0 ng/dL (hazard ratio of 2.23; p = 0.0117), and PSA ≥ 28.9 ng/mL (hazard ratio of 2.36; p = 0.0097) were significant poor prognostic factors in the multivariate analysis. The results of the two-group analysis showed that a higher Hs-mGPS was associated with high PSA, alkaline phosphatase, and testosterone levels. The median testosterone levels for Hs-mGPS of 0, 1, and 2 were 9.0, 16.5, and 23.0, respectively. Based on the multivariate analysis, we created a combined score with three prognostic factors: Hs-mGPS, testosterone, and PSA. The low-risk group (score of 0-1) showed a significantly longer overall survival compared to the intermediate-risk (score of 2-3) and high-risk (score of 4) groups (p < 0.0001). Our results demonstrated that an elevated Hs-mGPS was an independent prognostic factor in CRPC patients treated with docetaxel therapy. Risk classification based on Hs-mGPS, testosterone, and PSA may be useful in predicting the prognosis of CRPC patients.

The heavy chain of 4F2 antigen promote prostate cancer progression via SKP-2.

The 4F2 cell-surface antigen heavy chain (4F2hc) forms a heterodimeric complex with L-type amino acid transporter 1 (LAT1) and transports large neutral essential amino acids. However, in contrast to the traditional role of LAT1 in various cancers, the role of 4F2hc has largely remained unknown. The role of 4F2hc in prostate cancer was studied. Treatment of C4-2 cells with si4F2hc was found to suppress cellular growth, migratory and invasive abilities, with this effect occurring through the cell cycle, with a significant decrease in S phase and a significant increase in G0/G1 phase, suggesting cell cycle arrest. In addition, it was proven by RNA seq that the key to 4F2hc's impact on cancer is SKP2. si4F2hc upregulates the protein expression of cyclin-dependent kinase inhibitors (P21cip1, P27kip1) through the downstream target SKP2. Furthermore, the expression of 4F2hc and LAT1 in prostate cancer cells suggests the importance of 4F2hc. Multivariate analysis showed that high 4F2hc expression was an independent prognostic factor for progression-free survival (HR 11.54, p = 0.0357). High 4F2hc was related to the clinical tumour stage (p = 0.0255) and Gleason score (p = 0.0035). Collectively, 4F2hc contributed significantly to prostate cancer (PC) progression. 4F2hc may be a novel marker and therapeutic target in PC.

Expression of L-type amino acid transporter 1 as a molecular target for prognostic and therapeutic indicators in bladder carcinoma.

L-type amino acid transporter 1 (LAT1) plays a role in transporting essential amino acids including leucine, which regulates the mTOR signaling pathway. Here, we studied the expression profile and functional role of LAT1 in bladder cancer. Furthermore, the pharmacological activity of JPH203, a specific inhibitor of LAT1, was studied in bladder cancer. LAT1 expression in bladder cancer cells was higher than that in normal cells. SiLAT1 and JPH203 suppressed cell proliferative and migratory and invasive abilities in bladder cancer cells. JPH203 inhibited leucine uptake by > 90%. RNA-seq analysis identified insulin-like growth factor-binding protein-5 (IGFBP-5) as a downstream target of JPH203. JPH203 inhibited phosphorylation of MAPK / Erk, AKT, p70S6K and 4EBP-1. Multivariate analysis revealed that high LAT1 expression was found as an independent prognostic factor for overall survival (HR3.46 P = 0.0204). Patients with high LAT1 and IGFBP-5 expression had significantly shorter overall survival periods than those with low expression (P = 0.0005). High LAT1 was related to the high Grade, pathological T stage, LDH, and NLR. Collectively, LAT1 significantly contributed to bladder cancer progression. Targeting LAT1 by JPH203 may represent a novel therapeutic option in bladder cancer treatment.

Characterization of the expression of LAT1 as a prognostic indicator and a therapeutic target in renal cell carcinoma.

Large neutral amino acid transporter 1 (LAT1, SLC7A5) is abundantly expressed in various types of cancer, and it has been thought to assist cancer progression through its activity for uptake of neutral amino acids. However, the roles of LAT1 in renal cell carcinoma (RCC) prognosis and treatment remain uncharacterized. Therefore, we first retrospectively examined the LAT1 expression profile and its associations with clinical factors in RCC tissues (n = 92). The results of immunohistochemistry showed that most of the tissues examined (92%) had cancer-associated LAT1 expression. Furthermore, the overall survival (OS) and progression-free survival (PFS) were shorter in patients with high LAT1 expression levels than in those with low LAT1 expression levels (P = 0.018 and 0.014, respectively), and these associations were further strengthened by the results of univariate and multivariate analyses. Next, we tested the effects of JPH203, which is a selective LAT1 inhibitor, on RCC-derived Caki-1 and ACHN cells. It was found that JPH203 inhibited the growth of these cell types in a dose-dependent manner. Moreover, JPH203 clearly suppressed their migration and invasion activities. Thus, our results show that LAT1 has a great potential to become not only a prognosis biomarker but also a therapeutic target in RCC clinical settings.