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The role of the PTEN/mTOR axis in clinical response of rectal cancer patients

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Abstract

Background

Preoperative chemoradiotherapy has long been accepted as a method to improve survival and lifetime quality of rectal cancer patients. However, physiologic effects of these therapies largely depend on the resistance of cells to the radiation, type of chemotherapeutic agents and individual responses. As one of the signaling cascades involved in chemo- or radiation- resistance, the present study focused on several proteins involved in pTEN/Akt/mTOR pathway to explore their prognostic significance.

Materials and methods

Samples from advanced stage rectal cancer patients were analyzed to detect expression levels of pTEN/Akt/mTOR pathway related proteins pTEN, mLST8, REDD1, BNIP3, SAG and NOXA, together with p53, by RT-qPCR. Kaplan–Meier analysis was used to assess expression-survival relation and correlations among all proteins and clinicopathological features were statistically analyzed.

Results.

Except p53, none of the proteins showed prognostic significance. High p53 expression presented clear impact on overall survival and disease free survival. It was also significantly related to pathologic complete response. p53 showed high correlation to local recurrence as well. On the other hand, strong correlation was observed with PTEN expression and tumor response, but not with survival. High associations were also observed between mLST8/REDD1, PTEN and NOXA, confirming their role in the same cascade.

Conclusion

The contentious role of p53 as a prognostic biomarker in colorectal cancer was further affirmed, while PTEN and REDD1 could be suggested as potential candidates. Additionally, NOXA emerges as a conjunctive element for different signaling pathways.

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Acknowledgements

We thank Dr. Esra AKDENIZ for her valuable contribution on biostatistical evaluations.

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The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

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Authors and Affiliations

  1. Department of Biophysics, School of Medicine, Marmara University, Maltepe Basibuyuk Yolu Sok. 9/1, Maltepe, 34854, Istanbul, Turkey

    Oya Orun, Olca Kılınç, Pınar Mega Tiber & Pelin Yonar

  2. Clinic of Radiation Oncology, Dr. Lutfi Kirdar Kartal Training and Research Hospital, Istanbul, Turkey

    Sevgi Özden & Hazan Özyurt

  3. Department of Radiation Oncology, School of Medicine, Marmara University, Istanbul, Turkey

    Zerrin Özgen

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  1. Oya Orun
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Contributions

All authors contributed to the study conception and design. SÖ, ZÖ and HÖ: material preparation and all clinical applications; PY, OK and PMT: all experimental, data collection and analyses; OO: conception, management of the project, preparation of the first draft of the manuscript all authors commented on previous versions of the manuscript, read and approved the final form.

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Correspondence to Oya Orun.

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The authors have no relevant financial or non-financial interests to disclose.

Ethics approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Marmara University School of Medicine Ethics Board; with Protocol Number: 09.2015.275; Date: 02.10.2015.

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Supplementary Information

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11033_2022_7665_MOESM1_ESM.tif

Supplementary file1 (TIF 803 KB) Supplementary Figure S1 Representative network of PTEN/mTOR axis proteins involved in this study: (a) mTOR is an element in growth factor induction, but also regulated by nutrient depletion, hypoxia and energy stresses. mTORC1 activity relies on GTP-loaded Rheb and this interaction could be inhibited during hypoxia by BNIP3 (b) Hypoxia also inhibits mTORC1 through REDD1/DDIT4 dependent TSC1/TSC2 complex activity as a GTPase (GAP) for Rheb (c) p53 downregulates mTOR pathway through induction of PTEN, TSC2 and REDD1. Akt-Mdm2-p53 forms a negative-loop for p53 regulation, while PTEN-Akt-Mdm2-p53 forms a positive feedback. (d) mLST8 is a scaffolding element for both complexes. It reduces mTORC2 mediated phosphorylation of Akt and inhibits 4E-BP1 phosphorylation in cancer cells. (e) SAG is a component of SCF E3 Ubq ligase, actively involved in DEPTOR degradation, as well as it shows anti-apoptotic effect through NOXA degradation. SAG expression is also induced by hypoxia through HIF-1. Kaplan-Meier analysis of p53 and 10-year overall survival, together with Spearman correlations represented in Figure 1 and Table 3 were also summarized at the right column

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Orun, O., Özden, S., Kılınç, O. et al. The role of the PTEN/mTOR axis in clinical response of rectal cancer patients. Mol Biol Rep 49, 8461–8472 (2022). https://doi.org/10.1007/s11033-022-07665-x

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