Identifying and treating ROBO1−ve/DOCK1+ve prostate cancer: An aggressive cancer subtype prevalent in African American patients

Ferrari, Marina G.; Ganaie, Arsheed A.; Shabenah, Ashraf; Mansini, Adrián P.; Wang, Li; Murugan, Paari; Davicioni, Elai; Wang, Jinhua; Deng, Yibin; Hoeppner, Luke H.; Warlick, Christopher A.; Konety, Badrinath R.; Saleem, Mohammad

doi:10.1002/pros.24018

Cited by 5 publications

(3 citation statements)

References 35 publications

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“…Parray et al showed that ROBO1 negatively regulates motility and the invasiveness of primary prostate cancer cells, and its loss causes these cells to acquire invasive traits (21). Ferrari et al (22) reported that loss of ROBO1 causes disintegration of the DOCK1 complex that in turn triggers invasiveness of cancer cells through loss of E-Cadherin and activation of Rac1 signaling However, our results were different from those of Parray's. The present study showed that the knockdown of ROBO1 expression in prostate cancer cells resulted in a decreased capacity for migration and invasiveness.…”

Section: Discussioncontrasting

confidence: 91%

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ROBO1 protein expression is independently associated with biochemical recurrence in prostate cancer patients who underwent radical prostatectomy in Asian patients

Kim

Shin

et al. 2021

Gland Surg

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Background: The purpose of this study is to investigate the correlation between ROBO1 expression and prostate cancer aggressiveness Methods: ROBO1 expression was evaluated in normal prostate epithelial cells (PrEC) and different prostate cancer cell lines by Western blot analysis. The migration and invasion of native and ROBO1 knockdown cells were evaluated using migration chambers and a Matrigel-coated membrane, respectively. Samples from 145 patients who underwent radical prostatectomy between June 2000 and June 2008, were retrieved from the paraffin files for tissue microarray (TMA) with immunohistochemical analysis. Biochemical recurrence (BCR)-free survival curves were estimated using the Kaplan-Meier and Cox regression methods in two groups of patients classified according to the degree of ROBO1 expression (low or high expression).Results: ROBO1 is highly expressed in the prostate cancer cell lines. All ROBO1 knockdown cells (PC3, 22Rv1 and DU 145) showed markedly decreased migration and invasiveness compared to native cells. In 145 patients with radical prostatectomy, the Kaplan-Meier curves and log-rank test for BCR-free survival stratified by ROBO1 expression in organ-confined (pT2) or not (pT3), showed significant differences in 10-year survival between the ROBO1 high and low expression groups (87.2% versus 52.6% in pT2; P=0.047, 51.0% versus 36.9% in pT3; P=0.033). The multivariable-adjusted model showed a markedly increased hazard ratio (HR) in patients with high ROBO1 expression compared to the patients with low ROBO1expression in every model.Conclusions: ROBO1 may play an important role in the migration and invasion of prostate cancer cells, and was independently associated with BCR.

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Section: Discussioncontrasting

confidence: 91%

“…Current study suggested the clinical significance of ROBO1 expression based on the long-term oncological analysis. Comparing with the results of Ferrari et al (22), current analysis through the stratified stage and relatively large numbers of patients might be a distinction.…”

Section: Discussionmentioning

confidence: 42%

ROBO1 protein expression is independently associated with biochemical recurrence in prostate cancer patients who underwent radical prostatectomy in Asian patients

Kim

Shin

et al. 2021

Gland Surg

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“…CPYPP, a DOCK (dedicator of cytokinesis) inhibitor known for its anti-cancer effects by disrupting the interaction between DOCK2 and Rac1 [ 24 – 26 ], as well as CsA and curcumin, induced significant cytoplasmic vacuolization (Fig. 1 A).…”

Section: Resultsmentioning

confidence: 99%

CDK7/CDK9 mediates transcriptional activation to prime paraptosis in cancer cells

Chiang,

Chang,

Chen

et al. 2024

Cell Biosci

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Background Paraptosis is a programmed cell death characterized by cytoplasmic vacuolation, which has been explored as an alternative method for cancer treatment and is associated with cancer resistance. However, the mechanisms underlying the progression of paraptosis in cancer cells remain largely unknown. Methods Paraptosis-inducing agents, CPYPP, cyclosporin A, and curcumin, were utilized to investigate the underlying mechanism of paraptosis. Next-generation sequencing and liquid chromatography-mass spectrometry analysis revealed significant changes in gene and protein expressions. Pharmacological and genetic approaches were employed to elucidate the transcriptional events related to paraptosis. Xenograft mouse models were employed to evaluate the potential of paraptosis as an anti-cancer strategy. Results CPYPP, cyclosporin A, and curcumin induced cytoplasmic vacuolization and triggered paraptosis in cancer cells. The paraptotic program involved reactive oxygen species (ROS) provocation and the activation of proteostatic dynamics, leading to transcriptional activation associated with redox homeostasis and proteostasis. Both pharmacological and genetic approaches suggested that cyclin-dependent kinase (CDK) 7/9 drive paraptotic progression in a mutually-dependent manner with heat shock proteins (HSPs). Proteostatic stress, such as accumulated cysteine-thiols, HSPs, ubiquitin-proteasome system, endoplasmic reticulum stress, and unfolded protein response, as well as ROS provocation primarily within the nucleus, enforced CDK7/CDK9–Rpb1 (RNAPII subunit B1) activation by potentiating its interaction with HSPs and protein kinase R in a forward loop, amplifying transcriptional regulation and thereby exacerbating proteotoxicity leading to initiate paraptosis. The xenograft mouse models of MDA-MB-231 breast cancer and docetaxel-resistant OECM-1 head and neck cancer cells further confirmed the induction of paraptosis against tumor growth. Conclusions We propose a novel regulatory paradigm in which the activation of CDK7/CDK9–Rpb1 by nuclear proteostatic stress mediates transcriptional regulation to prime cancer cell paraptosis. Graphical Abstract

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Genetic and biological drivers of prostate cancer disparities in Black men

Gong,

Kim,

Freeman

et al. 2023

Nat Rev Urol

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Identifying and treating ROBO1^−ve/DOCK1^+ve prostate cancer: An aggressive cancer subtype prevalent in African American patients

Cited by 5 publications

References 35 publications

ROBO1 protein expression is independently associated with biochemical recurrence in prostate cancer patients who underwent radical prostatectomy in Asian patients

ROBO1 protein expression is independently associated with biochemical recurrence in prostate cancer patients who underwent radical prostatectomy in Asian patients

CDK7/CDK9 mediates transcriptional activation to prime paraptosis in cancer cells

Genetic and biological drivers of prostate cancer disparities in Black men

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