Integrated stress response-upregulated mitochondrial SLC1A5var enhances glucose dependency in human breast cancer cells in vitro

Sheng-Fan Wang; Yu-Chieh Ho; Chian-Ying Chou; Yuh-Lih Chang; Hsin-Chen Lee; Ling-Ming Tseng

doi:10.1016/j.biocel.2024.106688

Integrated stress response-upregulated mitochondrial SLC1A5var enhances glucose dependency in human breast cancer cells in vitro

Int J Biochem Cell Biol. 2024 Dec:177:106688. doi: 10.1016/j.biocel.2024.106688. Epub 2024 Nov 4.

Authors

Sheng-Fan Wang¹, Yu-Chieh Ho², Chian-Ying Chou³, Yuh-Lih Chang⁴, Hsin-Chen Lee⁵, Ling-Ming Tseng⁶

Affiliations

¹ Department of Pharmacy, Taipei Veterans General Hospital, No. 201, Section 2, Shipai Rd., Beitou Dist., Taipei 112, Taiwan; School of Pharmacy, Taipei Medical University, No. 250, Wuxing St., Xinyi Dist., Taipei 110, Taiwan; Department and Institute of Pharmacology, College of Medicine, National Yang-Ming Chiao-Tung University, No. 155, Section 2, Li-Nong St., Beitou Dist., Taipei 112, Taiwan; Institute of Biopharmaceutical Sciences, College of Pharmaceutical Sciences, National Yang-Ming Chiao-Tung University, No. 155, Section 2, Li-Nong St., Beitou Dist., Taipei 112, Taiwan. Electronic address: sfwang5@vghtpe.gov.tw.
² Department and Institute of Pharmacology, College of Medicine, National Yang-Ming Chiao-Tung University, No. 155, Section 2, Li-Nong St., Beitou Dist., Taipei 112, Taiwan. Electronic address: jenny030142@gmail.com.
³ Department of Pharmacy, Taipei Veterans General Hospital, No. 201, Section 2, Shipai Rd., Beitou Dist., Taipei 112, Taiwan; Department of Pharmacy, College of Pharmaceutical Sciences, National Yang-Ming Chiao-Tung University, No. 155, Section 2, Li-Nong St., Beitou Dist., Taipei 112, Taiwan. Electronic address: choucy@vghtpe.gov.tw.
⁴ Department of Pharmacy, Taipei Veterans General Hospital, No. 201, Section 2, Shipai Rd., Beitou Dist., Taipei 112, Taiwan; Department of Pharmacy, College of Pharmaceutical Sciences, National Yang-Ming Chiao-Tung University, No. 155, Section 2, Li-Nong St., Beitou Dist., Taipei 112, Taiwan. Electronic address: ylchang@vghtpe.gov.tw.
⁵ Department and Institute of Pharmacology, College of Medicine, National Yang-Ming Chiao-Tung University, No. 155, Section 2, Li-Nong St., Beitou Dist., Taipei 112, Taiwan; Department of Pharmacy, College of Pharmaceutical Sciences, National Yang-Ming Chiao-Tung University, No. 155, Section 2, Li-Nong St., Beitou Dist., Taipei 112, Taiwan; Department of Medical Research, Taipei Veterans General Hospital, No. 201, Section 2, Shipai Rd., Beitou Dist., Taipei 112, Taiwan. Electronic address: hclee2@nycu.edu.tw.
⁶ Division of General Surgery, Department of Surgery, Comprehensive Breast Health Center, Taipei Veterans General Hospital, No. 201, Section 2, Shipai Rd., Beitou Dist., Taipei 112, Taiwan; Department of Surgery, College of Medicine, National Yang-Ming Chiao-Tung University, No. 155, Section 2, Li-Nong St., Beitou Dist., Taipei 112, Taiwan. Electronic address: lmtseng@vghtpe.gov.tw.

PMID: 39505107
DOI: 10.1016/j.biocel.2024.106688

Abstract

Breast cancer is the most commonly diagnosed cancer among women. The growth of triple-negative breast cancer (TNBC) cells is glucose-dependent. The integrated stress response (ISR) is a cellular stress response to glucose depletion. The ISR-solute carrier family 7 member 11 pathway is activated during glucose depletion and contributes to glucose dependence by decreasing intracellular glutamate levels. Solute carrier family 1 member 5 (SLC1A5) and the mitochondrial solute carrier family 1 member 5 variant (SLC1A5var) are glutamine transporters that play essential roles in the reprogramming of cancer metabolism. However, whether ISR can regulate mitochondrial SLC1A5var expression and further affect glucose dependence remains unclear. Glucose depletion-, oligomycin-, and salubrinal-activated activating transcription factor-4 (ATF4) induced SLC1A5var expression. ATF4 is critical for SLC1A5var regulation, as it binds to specific regulatory elements in its promoter. SLC1A5var knockdown decreases glucose depletion-induced cell death, whereas SLC1A5var overexpression increases glucose depletion-induced cell death in TNBC cells. SLC1A5var knockdown reduced cancer cell proliferation, colony formation, and migration, whereas SLC1A5var overexpression increased cell proliferation and migration. Moreover, the knockdown of SLC1A5var reduces the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) while increasing the maximal OCR and ECAR under glucose depletion. These results suggest that activated ISR-induced increased expression of SLC1A5var may regulate mitochondrial oxidative phosphorylation and glycolytic metabolic characteristics to enhance glucose depletion-induced cell death. In conclusion, SLC1A5var plays a vital role in metabolic reprogramming and may be a potential target for breast cancer treatment.

Keywords: Breast cancer; Glucose dependency; Integrated stress response; Metabolism reprogramming; Solute carrier family 1 member 5 variant.

MeSH terms

Activating Transcription Factor 4 / genetics
Activating Transcription Factor 4 / metabolism
Amino Acid Transport System ASC / genetics
Amino Acid Transport System ASC / metabolism
Breast Neoplasms / genetics
Breast Neoplasms / metabolism
Breast Neoplasms / pathology
Cell Line, Tumor
Cell Proliferation
Female
Gene Expression Regulation, Neoplastic
Glucose* / metabolism
Humans
Minor Histocompatibility Antigens / genetics
Minor Histocompatibility Antigens / metabolism
Mitochondria* / genetics
Mitochondria* / metabolism
Mitochondria* / pathology
Stress, Physiological / genetics
Triple Negative Breast Neoplasms* / genetics
Triple Negative Breast Neoplasms* / metabolism
Triple Negative Breast Neoplasms* / pathology
Up-Regulation

Substances

Glucose
SLC1A5 protein, human
Activating Transcription Factor 4
Minor Histocompatibility Antigens
Amino Acid Transport System ASC
ATF4 protein, human