【ZOOM SEMINAR】Cancer stem cells: targets for cancer eradication

Dear All,

We would like to hold a ZOOM SEMINAR at ROOM C016 (Lab1, Level C).

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Dear All,

Cell Signal Unit (Yamamoto Unit) would like to inform you of a seminar by Dr. Hideyuki Saya from Keio University School of Medicine.

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Date: Wednesday, March 18, 2020

Time: 13:00-14:00

Venue: C016, Level C, Lab 1

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Speaker:

Dr. Hideyuki Saya, Keio University School of Medicine

Title:
Cancer stem cells: targets for cancer eradication

Abstract:
Tumors comprise heterogeneous cell types, including cancer stem cells (CSCs), progenitor cells, and differentiated cells. Chemoresistance is a major issue in cancer therapy that be a potential cause of relapse and is a key characteristic of CSCs, but the development of novel therapeutic approaches for targeting these cells are limited. We found that expression of a CSC marker, CD44, in particular variant forms of CD44 (CD44v), contributes to the defense against reactive oxygen species (ROS) by promoting the synthesis of reduced gluathione (GSH), a primary intracellular antioxidant. CD44v interacts with and stabilizes xCT, a subunit of a glutamate-cystine transporter, and thereby promotes the uptake of cystine for GSH synthesis¹⁾. Therefore, ablation of CD44 reduced GSH levels and increased ROS levels, leading to suppression of tumor growth and metastasis in both transgenic and xenograft tumor models^2,3). Based on these preclinical findings, we conducted clinical trials using an xCT inhibitor for cancer patients^4,5).

The efficacy of xCT-targeted therapy has been found to be diminished by metabolic reprogramming that affects redox status in cancer cells. The identification of drugs for combination with xCT inhibitors that are able to overcome resistance to xCT-targeted therapy thus provides the basis for effective cancer treatment⁶⁾. We have now identified the vasodilator oxyfedrine (OXY) as a sensitizer of cancer cells to GSH-depleting agents including the xCT inhibitor sulfasalazine (SSZ). OXY contains a structural motif required for covalent inhibition of aldehyde dehydrogenase enzymes, and combined treatment with OXY and SSZ was found to induce accumulation of the cytotoxic aldehyde 4-hydroxynonenal and cell death in SSZ-resistant cancer cells⁷⁾. Furthermore, OXY-mediated ALDH inhibition was found to sensitize cancer cells to GSH depletion induced by radiation therapy in vitro. Our findings thus establish a rationale for repurposing of OXY as a sensitizing drug for refractory cancer treatment with agents that induce GSH depletion.

References

1. Ishimoto T et al. Cancer Cell 19: 387-400, 2011
2. Yae T et al. Nat Commun 3: 883, 2012
3. Yoshikawa M et al. Cancer Res 73: 1855-1866, 2013
4. Shitara K et al. Gastric Cancer 20: 341-349, 2017
5. Otsubo K et al. Cancer Sci 108: 1843-1849, 2017
6. Okazaki S et al. Oncotarget 9: 33832-33843, 2018
7. Otsuki Y et al. Cancer Sci 111: 127-136, 2020

Host:
Prof. Tadashi Yamamoto

We hope to see many of you at the seminar.

Best regards,

Yuki Nakagawa

Research Unit Administrator

Cell Signal Unit