Impact of Oncogenic Changes in p53 and KRAS on Macropinocytosis and Ferroptosis in Colon Cancer Cells - Niclosamide’s Anticancer Efficacy with Differential Effects

Q: How do p53 deletion and KRAS activation differentially affect SLC7A11 and SLC38A5?

p53 deletion primarily induces SLC7A11, while KRAS activation induces both SLC7A11 and SLC38A5, linking transporter changes to ferroptosis and macropinocytosis regulation.

Q: What is the role of SLC7A11 in relation to ferroptosis in this study?

SLC7A11 induction strengthens antioxidant machinery and protects cancer cells from ferroptosis, highlighting its functional contribution to resistance against lipid-peroxidation-driven death.

Q: How does niclosamide influence macropinocytosis and ferroptosis?

Niclosamide blocks the functions of both SLC7A11 and SLC38A5, inducing ferroptosis while suppressing macropinocytosis, which counteracts tumor-promoting effects driven by p53 and KRAS changes.

Sep 22, 2026

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Mutations in p53 and KRAS frequently occur in colon cancer, yet their influence on amino-acid transporters remained insufficiently defined. Using isogenic colon cancer cell lines, the study evaluated p53 deletion and KRAS activation effects on SLC38A5 (macropinocytosis) and SLC7A11 (ferroptosis). p53 deletion primarily induced SLC7A11, enhancing antioxidant defenses and protecting cells from ferroptosis. KRAS activation increased both transporters, supporting ferroptosis resistance and accelerating macropinocytosis to improve amino-acid nutrition. Niclosamide blocked SLC7A11 and SLC38A5, inducing ferroptosis and suppressing macropinocytosis, thereby reversing tumor-promoting effects.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages27

Reading Time1 h 8 min

AccessFree to download

Introduction

Materials and Methods

Cell models and genetic manipulation

Transporter targets and functional assays

Results

Effects on macropinocytosis and ferroptosis

Role of p53 deletion and KRAS activation

Niclosamide differential impact on both processes

Discussion

Conclusions

cells Article 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 Nhi T. Nguyen, Souad R. Sennoune , Gunadharini Dharmalingam-Nandagopal, Sathish Sivaprakasam , Yangzom D. Bhutia and Vadivel Ganapathy * Citation: 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. Cells 2024, 13, 951. [https://](https://)[ ](https://)[doi.org/10.3390/cells13110951](doi.org/10.3390/cells13110951) Academic Editor: Xinbin Chen Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; [nhi.t.nguyen@ttuhsc.edu](nhi.t.nguyen@ttuhsc.edu) (N.T.N.); [souad.sennoune@ttuhsc.edu](souad.sennoune@ttuhsc.edu) (S.R.S.); [gnandago@ttuhsc.edu](gnandago@ttuhsc.edu) (G.D.-N.); [sathish.sivaprakasam@ttuhsc.edu](sathish.sivaprakasam@ttuhsc.edu) (S.S.); [yangzom.d.bhutia@ttuhsc.edu](yangzom.d.bhutia@ttuhsc.edu) (Y.D.B.) * [Correspondence: vadivel.ganapathy@ttuhsc.edu](Correspondence: vadivel.ganapathy@ttuhsc.edu) 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 macropinocytosisand ferroptosis, two processes with opposing effects on tumor growth. Here, we used isogenic colon cancer cell lines to investigate the effects of p53 deletion and KRAS activation on two amino acid transporters relevant to macropinocytosis (SLC38A5) and ferroptosis (SLC7A11) . Our studies show that the predominant effect of p53 deletion is to induce SLC7A11 with the 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 the resultant effective reversal of tumor-promoting actions of oncogenic changes in p53 and KRAS. These findings underscore the potential of this drug in colon cancer treatment. Keywords: p53 deletion; KRAS mutation; SLC7A11; SLC38A5; ferroptosis; macropinocytosis; antioxidant machinery; lipid peroxidation; niclosamide; colon cancer 1. Introduction Received: 31 March 2024 Revised: 25 May 2024 Accepted: 29 May 2024 Published: 30 May 2024 Copyright: © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) . As per the most recent colorectal cancer statistics of 2023, colorectal cancer is the third most commonly diagnosed cancer in men and women in the United States [1–3] . It is also the cause of the second most cancer-related deaths in men and the most prominent cause of cancer-related deaths in younger men (<50 years of age) . Colorectal cancer is the cause of approximately one million deaths worldwide every year. There are several risk factors for colorectal cancer, including age, sex, family history, diet, inflammation, and gene mutations. Truly alarming is the estimate that about 4% of men and women will be di

FAQs

How do p53 deletion and KRAS activation differentially affect SLC7A11 and SLC38A5?

p53 deletion primarily induces SLC7A11, while KRAS activation induces both SLC7A11 and SLC38A5, linking transporter changes to ferroptosis and macropinocytosis regulation.

What is the role of SLC7A11 in relation to ferroptosis in this study?

SLC7A11 induction strengthens antioxidant machinery and protects cancer cells from ferroptosis, highlighting its functional contribution to resistance against lipid-peroxidation-driven death.

How does niclosamide influence macropinocytosis and ferroptosis?

Niclosamide blocks the functions of both SLC7A11 and SLC38A5, inducing ferroptosis while suppressing macropinocytosis, which counteracts tumor-promoting effects driven by p53 and KRAS changes.

Sep 22, 2026

Upload by Maeve