Protein Arginine Methyltransferases in Pancreatic Ductal Adenocarcinoma: New Molecular Targets for Therapy
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsAbstract
Says: under cancer clinical trials
Suggestion: under clinical trials
Says: and have the potential to become new generation of cancer therapeutics.
Suggestion: that can potentially become a new generation of anti-cancer drugs.
1.- Modify title to
1.- Introduction: Pancreatic Ductal Adenocarcinoma and the Need for New Therapeutics
Says: major type of pancreatic neoplasm of ductal origin
Suggestion: modify this sentence. PDAC can be originated also from acinar cells.
Says: Approximately 80-85% of the patients are diagnosed with PDAC when the disease has already metastasized, making them ineligible for surgical resection
Suggestion: Approximately 80-85% of the patients are diagnosed with PDAC when the disease has already metastasized or became locally advanced, making them ineligible for surgical resection
Says: , 3 out of 4 patients develop recurrence
Suggestion: , 3 out of 4 patients will develop a relapse
Says: they all have to undergo intensive chemotherapy
Suggestion: they usually all undergo…
Says FLORFIRINOX
Change for FORFIRINOX
Says: which is the combination
Suggestion: which is the association
Says: Irinotecan in adjunct with 5-Fluorouracil
Suggestion: Irinotecan with 5-Fluorouracil
Says: if their disease is progressing during
Suggestion: if their disease progresses during
Line 47 correct FLORFIRINOX
Says: However, while the mutated KRAS protein is a “drug- gable” target using KRAS specific small molecule inhibitors
Suggest: However, while the mutated KRAS protein is a “drug gable” target using KRAS specific small molecule inhibitors (there are no FDA approved KRAS inhibitors for PDAC as yet)
Says: TP53, CDKN2A and SMAD4, also frequently occur in PDAC cells, which drive tumor progression independent of KRAS
Comment: I am not sure that TP53, CDKN2A and SMAD can drive tumor progression without an activated KRAS. While KRAS is an oncogene, the other three are tumor suppressor genes. Please add some more convincing references. I do not think Reference 14, Halbrook et al. is adequate for this.
To the best of my knowledge for PDAC progression you need an active (mutated) KRAS or EGFR or PDGFR or FGFR. Suppression of tumor suppressor genes is insufficient for PDAC. (This is a personal point of view).
Says: extracellular matrix (ECM) barrier, which contributes to the desmoplastic TME
Comment: the desmoplastic reaction IS the extracellular matrix barrier. Please modify the sentence.
Says: Recent advancement
Suggest: Recent advances
2. Arginine Methylation and PRMTs
Says: PRMTs are the writers of arginine
Question: what do you mean by writers? May be you want to say that PRMTs are the main arginine methylators?
Says: both nuclear as well as cytosolic compartment
Suggestion: both nuclear as well as cytosolic compartments
Says: While type I PRMTs are capable of forming
Suggestion: While type I PRMTs can form
Say: and type III PRMTs arecapable of forming mono-methyl arginine (MMA) only
Suggestion: and type III PRMTs can only produce mono-methyl arginine (MMA).
Change this sentence: The mechanism of arginine methylation by PRMTs is well described
Says: guanidino nitrogen atoms
Suggestion: guanidine nitrogen moieties
Says: All of the
Suggestion: All the
2.1. Structural Basis, Localization and Motif Preference of PRMTs
Suggestion: A figure showing the PRMTs structure would be convenient for the reader.
Says: have high likelihood of getting methylated
Suggestion: have high likelihood of being methylated
Says: with the SAM as a methyl donor to methylate their substrates.
Suggestion: with SAM as a methyl donor.
Says: majority of findings suggest
Suggestion: most findings suggest
2.2. Physiological Role of PRMTs
Says: therefore plays significant role
Suggestion: therefore plays a significant role
Says: as the writers of arginine methylation,
Comment: I do not understand what you want to say with the word writers. Please, be more clear on this point.
Says: , such as estrogen receptor
Comment: which estrogen receptor?
Says: histone proteins is able to
Suggestion: histone proteins can
Says: transcriptional coactivator
Suggestion: transcriptional co-activator
Says: Studies have revealed that some of the PRMTs, especially PRMT1, PRMT3, and PRMT5, are inti- mately associated with PDAC tumorigenesis, metastasis, and chemo-resistance.
Suggestion: It has been found that…
Comment: this sentence requires a reference.
Says: involving 90 patient tissue samples
Suggestion: involving tissue samples of 90 patients
Says: tissues compared with the adjacent normal
Suggestion: tissues compared to the adjacent normal
Says: and renders PDAC cells chemo-resistance
Suggestion: and renders PDAC cells chemo-resistant
Says: Studies have shown that PRMT3 upregulates expression of the multidrug resistant gene ABCG2 in PDAC cells, by enhancing the methylation of hnRNPA1 at the R31 residue that in turn increases the binding of hnRNPA1 to ABCG2 mRNA. The binding of hnRNA1 to ABCG2 mRNA facilitates its export to the cytoplasm and enhances its expression level, thereby causing chemo-resistance of PDAC cells.
Suggestion: this is an important sentence and needs a reference.
Says: It turns out that PRMT5 regulates the expression of cMyc at the post-transcriptional level by inhibiting the E3 protein ligase FBW7. Knockdown of PRMT5 in PDAC cells reduces the protein level of cMYC, without affecting its mRNA levels, attributing to an increased degradation of cMyc via the proteasomal degradation pathway facilitated by FBW7
Comment: this phrase requires a reference.
Says: the CDK2NA gene deletion often goes with co-deletion of its adjacent genes
Suggestion: the CDK2NA gene deletion is often associated with co-deletion of its adjacent genes
Says: heightening the sensitivity of cancer
Suggestion: increasing the sensitivity of cancer
5. Perspectives
Says: The arginine methylation of histone and non-histone proteins is not explored as well as other PTMs such as phosphorylation and glycosylation
Suggestion: The arginine methylation of histone and non-histone proteins has not been explored in depth.
Comments on the Quality of English LanguageIt needs some improvements
Author Response
We thank this reviewer for his/her thoroughness in reviewing our manuscript. We have addressed all concerns of this reviewer (see track-changed in the revision), and added a figure (Figure 2) to show the structure of PRMTs according to the suggestions.
Reviewer 2 Report
Comments and Suggestions for AuthorsThis is a very well written review that addresses the role of PRMTs in pancreatic cancer and also addresses the development of anti-cancer therapeutics based on these findings. The authors systematically address the role of different PRMTs in PDAC, starting with arginine metylation, then discussing different PRMT5s, and finally ending with the developed pharmacological inhibitors.
I have few concerns at the moment:
1) The authors could discuss the effects of PRMT inhibitors on normal cells in terms of clinical trials and in the context of normal pancreatic cells.
2) Most of the inhibitors in clinical trials are against PRMT5, only one is against PRMT1, and all other PRMTs are not targeted in clinical trials-- this can be discussed.
3) All clinical trials of PRMT inhibitors are not taking place in PDAC - the authors discuss some work in PDAC cell lines using combination therapies, but some more discussion of this issue will be beneficial.
4) I miss the summarizing signaling schemes showing how application of a particular inhibitor leads to apoptosis induction or inhibition of DNA repair or cell proliferation via inhibition of a particular PRMT enzyme. These need to be added to this review.
Author Response
We appreciate this reviewer’s positive comments and suggestions.
- The authors could discuss the effects of PRMT inhibitors on normal cells in terms of clinical trials and in the context of normal pancreatic cells.
Response: We have discussed the selective action of PRMT inhibitors towards cancer cells and added a corresponding reference (page 12/25, line 410-413).
- Most of the inhibitors in clinical trials are against PRMT5, only one is against PRMT1, and all other PRMTs are not targeted in clinical trials-- this can be discussed.
Response: We have added discussion on page 11/25, line 406.
- All clinical trials of PRMT inhibitors are not taking place in PDAC - the authors discuss some work in PDAC cell lines using combination therapies, but some more discussion of this issue will be beneficial.
Response: We have added discussion on page 13, line 490-495.
- I miss the summarizing signaling schemes showing how application of a particular inhibitor leads to apoptosis induction or inhibition of DNA repair or cell proliferation via inhibition of a particular PRMT enzyme. These need to be added to this review.
Response: We have added a figure (Figure 3) to indicate the anticancer action of the major PRMT inhibitors.
Round 2
Reviewer 2 Report
Comments and Suggestions for Authorsexcellent revisions: I do not have anymore comments