Weiguo Feng

Prostate cancer (PCa) is the most common malignancy among men worldwide. The cell division cycle 42 effector protein 4 (CDC42EP4) functions downstream of CDC42, yet its role and molecular mechanisms in PCa remain unexplored. This study aimed to elucidate the role of CDC42EP4 in the progression of PCa and its underlying mechanisms. Bioinformatical analysis indicated that CDC42EP4 expression was significantly lower in PCa tissue compared to normal prostate tissue. Cellular phenotyping analysis suggested that CDC42EP4 markedly inhibited the proliferation, migration, and invasion of PCa cells. Xenograft tumor assays further demonstrated that CDC42EP4 suppressed the growth of PCa cells in vivo. Mechanistically, the study established that CDC42EP4 inhibited the ERK pathway in PCa cells. Additionally, the ERK pathway inhibitor PD0325901 was employed, revealing that PD0325901 significantly nullified the effects of CDC42EP4 on PCa cell proliferation, migration, and invasion. Collectively, our findings demonstrate that CDC42EP4 acts as a critical tumor suppressor gene, inhibiting PCa cell proliferation, migration, and invasion through the ERK pathway, thereby presenting potential targets for PCa therapy.

Prostate cancer (PCa) is one of the most common malignancies in men. Ribosomal protein L22‐like1 (RPL22L1), a component of the ribosomal 60 S subunit, is associated with cancer progression, but the role and potential mechanism of RPL22L1 in PCa remain unclear. The aim of this study was to investigate the role of RPL22L1 in PCa progression and the mechanisms involved. Bioinformatics and immunohistochemistry analysis showed that the expression of RPL22L1 was significantly higher in PCa tissues than in normal prostate tissues. The cell function analysis revealed that RPL22L1 significantly promoted the proliferation, migration and invasion of PCa cells. The data of xenograft tumour assay suggested that the low expression of RPL22L1 inhibited the growth and invasion of PCa cells in vivo. Mechanistically, the results of Western blot proved that RPL22L1 activated PI3K/Akt/mTOR pathway in PCa cells. Additionally, LY294002, an inhibitor of PI3K/Akt pathway, was used to block this pathway. The results showed that LY294002 remarkably abrogated the oncogenic effect of RPL22L1 on PCa cell proliferation and invasion. Taken together, our study demonstrated that RPL22L1 is a key gene in PCa progression and promotes PCa cell proliferation and invasion via PI3K/Akt/mTOR pathway, thus potentially providing a new target for PCa therapy.

FN-1501 is a potent FLT3 inhibitor with antitumor activity. A phase 1 trial of FN-1501 monotherapy in patients with advanced solid tumors and R/R AML is in progress. Since one of the primary causes of multidrug resistance (MDR) is the overexpression of ATP-binding cassette superfamily B member 1 (ABCB1), the objective of this study was to investigate the potential relationship between FN-1501 and the ABCB1 transporter. We found ABCB1 overexpressing-cancer cells conferred FN-1501 resistance, which could be reversed by an ABCB1 inhibitor. Molecular docking study revealed that FN-1501 docked the ligand binding site with an affinity score of -9.77 kcal/ mol, denoting a strong interaction between FN-1501 and ABCB1. Additionally, the ABCB1 ATPase assay indicated that FN-1501 could significantly stimulate ABCB1 ATPase activity. Furthermore, we observed a similar trend of ABCB1-facilated FN-1501 resistance in tumor-bearing mice model. In sum, we demonstrate that FN-1501 is a substrate of ABCB1 transporter from both in vivo and in vitro studies. Therefore, our findings provide new insight on the mechanism of chemoresistance due to ABCB1 overexpression.

Microcystin‑leucine arginine (MC‑LR) is an environmental toxin produced by cyanobacteria and is considered to be a potent carcinogen. However, to the best of our knowledge, the effect of MC‑LR on colorectal cancer (CRC) cell proliferation has never been studied. The aim of the present study was to investigate the effect of MC‑LR on CRC cell proliferation and the underlying mechanisms. Firstly, a Cell Counting Kit‑8 (CCK‑8) assay was conducted to determine cell viability at different concentrations, and 50 nM MC‑LR was chosen for further study. Subsequently, a longer CCK‑8 assay and a cell colony formation assay showed that MC‑LR promoted SW620 and HT29 cell proliferation. Furthermore, western blotting analysis showed that MC‑LR significantly upregulated protein expression of PI3K, p‑Akt (Ser473), p‑GSK3β (Ser9), β‑catenin, c‑myc and cyclin D1, suggesting that MC‑LR activated the PI3K/Akt and Wnt/β‑catenin pathways in SW620 and HT29 cells. Finally, the pathway inhibitors LY294002 and ICG001 were used to validate the role of the PI3K/Akt and Wnt/β‑catenin pathways in MC‑LR‑accelerated cell proliferation. The results revealed that MC‑LR activated Wnt/β‑catenin through the PI3K/Akt pathway to promote cell proliferation. Taken together, these data showed that MC‑LR promoted CRC cell proliferation by activating the PI3K/Akt/Wnt/β‑catenin pathway. The present study provided a novel insight into the toxicological mechanism of MC‑LR.

Overexpression of ATP-binding cassette subfamily B member 1 (ABCB1) remains one of the most vital factors leading to multidrug resistance (MDR). It is important to enhance the effect and bioavailability of chemotherapeutic drugs that are substrates of ABCB1 transporter in ABCB1-overexpression cancer cells and reverse ABCB1-mediated MDR. Previous, we uncovered that the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib is a potent reversal agent to overcomes paclitaxel resistance in ABCB1-overexpressing cells and tumors. In this study, we explored whether RN486, another BTK inhibitor, was competent to surmount ABCB1-mediated MDR and promote relevant cancer chemotherapy. We found that RN486 significantly increased the efficacy of paclitaxel and doxorubicin in both drug-selected carcinoma cells and transfected cells overexpressing ABCB1. Mechanistic studies indicated that RN486 dramatically attenuated the drug efflux activity of ABCB1 transporter without altering its expression level or subcellular localization. The ATPase activity of ABCB1 transporter was not affected by low concentrations but stimulated by high concentrations of RN486. Moreover, an interaction between RN486 with ABCB1 substrate-binding and inhibitor binding sites was verified by in silico docking simulation. The results from our study suggest that RN486 could be a reversal agent and could be used in the novel combination therapy with other antineoplastic drugs to conquer MDR-mediated by ABCB1 transporter in clinics.

Microcystin-leucine arginine (MC-LR) is a potent tumor initiator that can induce malignant cell transformation. Cellular mechanical characteristics are pivotal parameters that are closely related to cell invasion. The aim of this study is to determine the effect of MC-LR on mechanical parameters, microfilament, and cell invasion in DU145 and WPMY cells. Firstly, 10 μM MC-LR was selected as the appropriate concentration via cell viability assay. Subsequently, after MC-LR treatment, the cellular deformability and viscoelastic parameters were tested using the micropipette aspiration technique. The results showed that MC-LR increased the cellular deformability, reduced the cellular viscoelastic parameter values, and caused the cells to become softer. Furthermore, microfilament and microfilament-associated proteins were examined by immunofluorescence and Western blot, respectively. Our results showed that MC-LR induced microfilament reorganization and increased the expression of p-VASP and p-ezrin. Finally, the impact of MC-LR on cell invasion was evaluated. The results revealed that MC-LR promoted cell invasion. Taken together, our results suggested that mechanical changes and microfilament reorganization were involved in MC-LR-promoted cell invasion in DU145 and WPMY cells. Our data provide novel information to explain the toxicological mechanism of MC-LR.