PreprintArticleVersion 2Preserved in Portico This version is not peer-reviewed
Impact of Oncogenic Changes in p53 and KRAS on Macropinocytosis and Ferroptosis in Colon Cancer Cells and Anticancer Efficacy of Niclosamide with Differential Effects on These Two Processes
Version 1
: Received: 1 April 2024 / Approved: 1 April 2024 / Online: 2 April 2024 (03:08:11 CEST)
Version 2
: Received: 3 April 2024 / Approved: 4 April 2024 / Online: 4 April 2024 (12:58:46 CEST)
How to cite:
Nguyen, N.T.; Sennoune, S.R.; Dharmalingam-Nandagopal, G.; Sivaprakasam, S.; Bhutia, Y.D.; Ganapathy, V. Impact of Oncogenic Changes in p53 and KRAS on Macropinocytosis and Ferroptosis in Colon Cancer Cells and Anticancer Efficacy of Niclosamide with Differential Effects on These Two Processes. Preprints2024, 2024040092. https://doi.org/10.20944/preprints202404.0092.v2
Nguyen, N.T.; Sennoune, S.R.; Dharmalingam-Nandagopal, G.; Sivaprakasam, S.; Bhutia, Y.D.; Ganapathy, V. Impact of Oncogenic Changes in p53 and KRAS on Macropinocytosis and Ferroptosis in Colon Cancer Cells and Anticancer Efficacy of Niclosamide with Differential Effects on These Two Processes. Preprints 2024, 2024040092. https://doi.org/10.20944/preprints202404.0092.v2
Nguyen, N.T.; Sennoune, S.R.; Dharmalingam-Nandagopal, G.; Sivaprakasam, S.; Bhutia, Y.D.; Ganapathy, V. Impact of Oncogenic Changes in p53 and KRAS on Macropinocytosis and Ferroptosis in Colon Cancer Cells and Anticancer Efficacy of Niclosamide with Differential Effects on These Two Processes. Preprints2024, 2024040092. https://doi.org/10.20944/preprints202404.0092.v2
APA Style
Nguyen, N.T., Sennoune, S.R., Dharmalingam-Nandagopal, G., Sivaprakasam, S., Bhutia, Y.D., & Ganapathy, V. (2024). Impact of Oncogenic Changes in p53 and KRAS on Macropinocytosis and Ferroptosis in Colon Cancer Cells and Anticancer Efficacy of Niclosamide with Differential Effects on These Two Processes. Preprints. https://doi.org/10.20944/preprints202404.0092.v2
Chicago/Turabian Style
Nguyen, N.T., Yangzom D. Bhutia and Vadivel Ganapathy. 2024 "Impact of Oncogenic Changes in p53 and KRAS on Macropinocytosis and Ferroptosis in Colon Cancer Cells and Anticancer Efficacy of Niclosamide with Differential Effects on These Two Processes" Preprints. https://doi.org/10.20944/preprints202404.0092.v2
Abstract
Mutations in p53 and KRAS are seen in most cases of colon cancer. The impact of these mutations on signaling pathways related to cancer growth has been studied in depth, but relatively less is known on their effects on amino acid transporters in cancer cells. This represents a significant knowledge gap because amino acid nutrition in cancer cells profoundly influences macropinocytosis and ferroptosis, two processes with opposing effects on tumor growth. Here we used isogenic colon cancer cell lines to investigate the effects of p53 loss and KRAS activation on two amino acid transporters relevant to macropinocytosis (SLC38A5) and ferroptosis (SLC7A11). Our studies show that the predominant effect of p53 loss is to induce SLC7A11 with resultant potentiation of antioxidant machinery and protection of cancer cells from ferroptosis whereas KRAS activation induces not only SLC7A11 but also SLC38A5, thus offering protection from ferroptosis as well as improving amino acid nutrition in cancer cells via accelerated macropinocytosis. Niclosamide, an FDA-approved anti-helminthic, blocks the functions of SLC7A11 and SLC38A5, thus inducing ferroptosis and suppressing macropinocytosis with resultant effective reversal of tumor-promoting actions of oncogenic mutations in p53 and KRAS. These findings underscore the potential of this drug in colon cancer treatment.
Biology and Life Sciences, Biochemistry and Molecular Biology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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