Exploring the Role of Surface and Mitochondrial ATP-Sensitive Potassium Channels in Cancer: From Cellular Functions to Therapeutic Potentials

Round 1

Reviewer 1 Report

Dear Editor,

I have reviewed the manuscript titled "Exploring the Role of Surface and Mitochondrial ATP-Sensitive Potassium Channels in Cancer: From Cellular Functions to Therapeutic Potentials," and I am pleased to recommend it for publication.

This manuscript is a well-written, comprehensive, and timely review of the current state of knowledge on the role of ATP-sensitive potassium channels in cancer. The authors have done an excellent job of organizing and presenting the material in a clear and logical way, with ample use of figures and tables to illustrate key concepts and findings.

One of the strengths of this manuscript is the depth and breadth of the research that the authors have included. They have done an excellent job of surveying the literature and incorporating a wide range of studies and findings, which provides a thorough and up-to-date picture of the field.

Another strength is the authors' ability to synthesize and integrate diverse sources of information, and to present complex concepts and ideas in a clear and understandable way. This makes the manuscript accessible and useful to a wide range of readers, from experts in the field to those who are less familiar with the topic.

I did notice one minor issue with the figure legend for Figure 1, which currently reads "Schematic Representation of Potassium's (K+) Role in Cancer Cell Physiology." I would suggest revising this legend to read "Schematic Representation of Potassium's (K+) Role in various cellular processes" to more accurately reflect the content of the figure.

Overall, I believe that this manuscript will make a valuable contribution to the literature and will be of interest to a broad audience of researchers and clinicians who are working on cancer and related topics. I recommend its publication in its current form.

Thank you for the opportunity to review this manuscript. Please let me know if you have any questions or concerns.

Author Response

Thank you for your thoughtful and kind review. I have addressed the issues highlighted in your minor comments.

Reviewer 2 Report

The manuscript of “Exploring the Role of Surface and Mitochondrial ATP-Sensitive Potassium Channels in Cancer: From Cellular Functions to Therapeutic Potentials by” Dong-Oh Moon aims to review common molecular mechanisms linking potassium transport via ATP-sensitive potassium channels with cancer cell physiology. The manuscript makes a contribution to the understanding of the involvement of the channels in the underlying mechanisms of cancer metabolism.

1.    The topic of the review is highly relevant due to the sharp increase in the number of cancer deaths and mortality rates worldwide and the urgent need to find new molecular targets for effective treatment. The author focused on a little-studied area of therapeutic significance of the pharmacological targeting of potassium channels localized on cytoplasmic and mitochondrial membranes in cancer. The review topic was fully covered.

2.    The manuscript as a whole and all its sections are well written and structured.

3.    This manuscript offers an in-depth exploration of the effects of KATP channel modulators on cancer cell signaling, cancer cell dynamics, and tissue responses. The main structural and functional features of two types of ATP-sensitive potassium channels (plasma membrane and mitochondrial), along with novel promising pharmacological approaches targeting these channels for the management of cancer are described in detail. All the conclusions are consistent with the evidence.

4.    The manuscript is well illustrated. All figures in the text properly show the data and are easy to interpret.

5.    The manuscript covers a large amount of literature data; the author has cited 117 articles, a significant portion of which have been published over the last five years. All the references are appropriate.

Comments:

1.      Lines 77-82 and throughout the text: the abbreviations used have not been deciphered. For example, IGF-1; ERK1/2, PI3K, ORAI1, ORAI3, TRPC1, TRPV6, etc. The author needs to provide a list of abbreviations or provide the full names of the proteins in the main text.

2.      As a small remark, it should be noted the absence of the author's own research in the References section. It would be nice if the author highlighted his own contribution to the current understanding of the potential of KATP channels as targets in cancer therapy.

Author Response

1.      Lines 77-82 and throughout the text: the abbreviations used have not been deciphered. For example, IGF-1; ERK1/2, PI3K, ORAI1, ORAI3, TRPC1, TRPV6, etc. The author needs to provide a list of abbreviations or provide the full names of the proteins in the main text.  -> Thank you for your thoughtful and kind review. I have addressed the issues highlighted in your minor comments.

Reviewer 3 Report

Please see the attached file

Comments for author File: Comments.pdf

Author Response

The review scrutinizes how KATP channels influence the metabolic, ionic balance and operational mechanisms within cancerous cells. The manuscript is a significant contribution for the interdisciplinary scientific community involved in this specific field.

⟶ Thank you very much for your kind review. Unfortunately, the revision period overlapped with my business trip, preventing me from fully addressing your requests. However, I have made every effort to make the necessary amendments. I would be grateful for your understanding and positive consideration of the changes made.

Specific comments

-The druggability concept of mitochondrial potassium channels is evaluated but the challenges and future directions of research deserve to be discussed more convincingly.

⟶ I have revised the conclusion section to reflect your requirements.

- Before targeting with drugs specific K+ channels in mitochondria, the review should focus more heavily on:

1) the type of mitochondrial potassium channel.

2) The presence of mitochondrial potassium channels in specific tissues.

3) the presence of the mitochondrial potassium channel in targeted tissue versus other tissue.

⟶ I have added the requested content to section 1.

- More information about posttranslational modifications of mitochondrial potassium channels is missing.

⟶ Posttranslational modifications typically involve changes made to the protein after its initial synthesis, such as phosphorylation, acetylation, or ubiquitination, which can affect the protein's function, localization, or stability. In the case of CCDC51, which constitutes the mitochondrial KATP channel, it has only been recently elucidated, and research on its posttranslational modifications has not yet been conducted. Therefore, I was unable to include this information.

- A main weakness of the review is that the authors don’t share with the reader their expertise in the field. More information about articles summarising their contribution would be highly appreciated.

⟶ Your requested content has been added to pages 16 and 17.

- Chapter describing the biological functions of potassium is very wordy and most information are available in excellent published reviews.

⟶ The content of Section 1 has been revised.

- Please replace figure 2 with a figure representing the details of the molecular structure: C.Zhao and R.Mac Kinnon -PNAS-2021

⟶ After reviewing the "Molecular Structure of an Open Human K_ATP Channel" paper you referenced, it appears this research focuses on the structure of the plasma membrane K_ATP channels, with no mention of mitochondrial K_ATP channel structures. Additionally, while quoting figures partially from published papers typically does not raise copyright issues, some journals may require permission documents, depending on their copyright policies. For consistency and to avoid potential copyright concerns, I recommend not proceeding with modifications to Figure 2. I hope you understand and appreciate your comprehension in this matter.