Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript by Gulkarov et al., entitled “ Abiraterone Acetate Affects Gene Expression Profile in a Human Male Neuronal Cell Line: Potential Mechanism for Cognitive Deficits with Prostate Cancer Therapy  “ demonstrates that the treatment of prostate cancer with Abiraterone Acetate is associated with the alteration of the gene  expression profile of human neuronal cell lines  and thereby contributes to  the development of neurological adverse effects in the form of cognitive in response to the treatment  of prostate cancer patients with Abiraterone Acetate. Although such adverse effects are noted in prostate cancer patients and the mechanisms the molecular action of with Abiraterone Acetate are known, however the authors provide an in vitro data confirming that the induction of Cognitive deficit is attributed to alteration of gene expression profile of the neural cells. The study seems to be interesting. The functional analysis of the identified genes are essential to investigate the mechanisms of Abiraterone Acetate and to investigate the key genes, which are responsible of the development of Abiraterone Acetate-induced Cognitive deficit. This can be done by inhibitory experiments using small molecules or siRNA.

Also, the abstract and the conclusion do not reflect the context of the study  

Comments on the Quality of English Language

Acceptable

Author Response

RE: Manuscript ID: life-4404948        Type of manuscript: Article

Title: Abiraterone Acetate Affects Gene Expression Profile in a Human Male Neuronal Cell Line: Potential Mechanism for Cognitive Deficits with Prostate Cancer Therapy

 

We thank the reviewer for thoroughly scrutinizing our manuscript. As requested, we have revised the manuscript and addressed the specific comments of the reviewer. The revised sections are delineated in red in a marked copy of the manuscript text.

 

Below, we provide a point-by-point response to the reviewer’s comments.

 

Reviewer # 1 Comments

• COMMENT #1: The manuscript by Gulkarov et al., entitled “ Abiraterone Acetate Affects Gene Expression Profile in a Human Male Neuronal Cell Line: Potential Mechanism for Cognitive Deficits with Prostate Cancer Therapy “ demonstrates that the treatment of prostate cancer with Abiraterone Acetate is associated with the alteration of the gene expression profile of human neuronal cell lines  and thereby contributes to  the development of neurological adverse effects in the form of cognitive in response to the treatment  of prostate cancer patients with Abiraterone Acetate. Although such adverse effects are noted in prostate cancer patients and the mechanisms the molecular action of with Abiraterone Acetate are known, however the authors provide an in vitro data confirming that the induction of Cognitive deficit is attributed to alteration of gene expression profile of the neural cells. The study seems to be interesting. The functional analysis of the identified genes are essential to investigate the mechanisms of Abiraterone Acetate and to investigate the key genes, which are responsible of the development of Abiraterone Acetate-induced Cognitive deficit. This can be done by inhibitory experiments using small molecules or siRNA.

RESPONSE: We thank the reviewer for their positive assessment of the study and for highlighting the importance of functional analyses of the differentially expressed genes identified in our neural cell model of abiraterone acetate–associated cognitive impairment. We fully agree that targeted siRNA knockdown, application of small molecule inhibitors or miRNA mimic gain-of-function approaches would be valuable to dissect the causal contribution of specific genes and pathways to the observed cognitive relevant phenotypes.

In the current work, our primary aim was to demonstrate that abiraterone acetate alters gene expression in neural cells in a manner consistent with cognitive dysfunction. In line with the scope of this study, we did not extend our experiments to mechanistic perturbation experiments. We have now explicitly acknowledged this as a limitation and have added text to the Discussion indicating that future studies will focus on the functional validation of key mitochondrial fission/fusion and synaptic plasticity candidate genes using siRNA and pharmacologic modulation in complementary neural models, to clarify their role in mediating abiraterone acetate–induced cognitive decline.

 

• COMMENT #2: Also, the abstract and the conclusion do not reflect the context of the study.

RESPONSE: We have revised the abstract and conclusion to better reflect study context.

 

We thank the reviewer and believe that the manuscript is improved as a result of their input. We hope you will agree and decide in favor of accepting our report at this time.

 

 

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The authors present a study investigating the changes in gene and protein expression that contribute to anti-androgen–related cognitive decline. A major limitation is that entire study is based on one particular cell line, BE(2)M17. Every cell line, particularly pathogenic cell lines including cancer cell lines, have varied expression of multiple biomarkers at both RNA and protein levels. Thereby, unless the findings are extended to minimum another cell line, the data is cell line-specific. The authors need to confirm their findings  in another prostate cancer cell line for the study to be validated across a cancer indication.

Author Response

RE: Manuscript ID: life-4404948        Type of manuscript: Article

Title: Abiraterone Acetate Affects Gene Expression Profile in a Human Male Neuronal Cell Line: Potential Mechanism for Cognitive Deficits with Prostate Cancer Therapy

 

We thank the reviewer for thoroughly scrutinizing our manuscript. As requested, we have revised the manuscript and addressed the specific comments of the reviewer. We have adjusted fonts and formatting of figures for clarity. The revised sections are delineated in red in a marked copy of the manuscript text.

 

Below, we provide a point-by-point response to the reviewer’s comments.

 

Reviewer # 2 Comments

• COMMENT #1: The authors present a study investigating the changes in gene and protein expression that contribute to anti-androgen–related cognitive decline. A major limitation is that entire study is based on one particular cell line, BE(2)M17. Every cell line, particularly pathogenic cell lines including cancer cell lines, have varied expression of multiple biomarkers at both RNA and protein levels. Thereby, unless the findings are extended to minimum another cell line, the data is cell line-specific. The authors need to confirm their findings in another prostate cancer cell line for the study to be validated across a cancer indication.

RESPONSE: We thank the reviewer for their thoughtful comments on our choice of cellular model and for highlighting the broader issue of cell line–specific biology. We would like to clarify that BE(2)-M17 is a male human neuroblastoma–derived neural cell line, rather than a prostate cancer cell line. This model was selected deliberately to reflect neuronal vulnerability and to enable investigation of how loss of androgen production affects cognitive mechanisms in a neural context. BE(2)M17 (derived from a male patient) provides a model with an active, male-typical genetic complement (XY) for study of androgen-related changes in gene expression. This ensures researchers observe specific androgen-receptor signaling mechanisms without the confounding effects of female-typical sex chromosomes (XX) or compensatory female epigenetic mechanisms, which is crucial for studying androgen-sensitive pathways.

     We agree that extending key observations to additional cellular models can strengthen generalizability, particularly across different disease indications. However, within the scope of the present study, our primary objective was to characterize abiraterone acetate–induced transcriptional and proteomic changes in neural cells relevant to cognitive impairment, rather than to interrogate cancer-specific biology. Future work will focus on validating the most robust mitochondrial and synaptic candidates in complementary neural systems and, where appropriate, in disease-relevant models to further assess the broader applicability of these findings.

     Further, the primary objective of this study was mechanistic rather than comparative across cell lines. Our analyses focus on identifying pathways and molecular responses to anti-androgen exposure, which are expected to reflect conserved biological processes rather than cell line–specific artifacts. Importantly, the observed changes are consistent with previously reported pathways implicated in cognitive impairment, supporting the broader relevance of our findings.

     While we agree that validation in additional models would further strengthen generalizability, performing a full replication in another cell line is beyond the scope of the current study. We have now explicitly acknowledged this as a limitation in the revised manuscript and have outlined it as an important direction for future work.

     To address the reviewer’s concern, we have added text in the Discussion clarifying the rationale for the selected model, its relevance in the field, and the need for future cross-model validation.

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We thank the reviewer and believe that the manuscript is improved as a result of their input.  We hope you will agree, and decide in favor of accepting our report at this time.

 

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript is now improved and can be published in the present form

Reviewer 2 Report

Comments and Suggestions for Authors

Hi,

The revised manuscript looks much better. The authors have addressed the majority of my concerns. Additionally, they have acknowledged the limitations of the study as well.

I recommend acceptance of the manuscript.