SIRT3-Mediated SOD2 and PGC-1α Contribute to Chemoresistance in Colorectal Cancer Cells.

Abstract

BACKGROUND:

Anticancer drugs generate excessive reactive oxygen species (ROS), which can cause cell death. Cancer cells can resist this oxidative stress, but the mechanism of resistance and associations with chemoresistance are unclear. Here, we focused on Sirtuin 3 (SIRT3), a deacetylating mitochondrial enzyme, in oxidative stress resistance in colorectal cancer (CRC).

METHODS:

To evaluate SIRT3-related changes in mitochondrial function, ROS (mtROS) induction, and apoptosis, we used the human CRC cell lines HT29 and HCT116 transfected with short-hairpin RNA targeting SIRT3 and small interfering RNAs targeting superoxide dismutase 2 mitochondrial (SOD2) and peroxisome proliferator-activated receptor γ coactivator-1 (PGC-1α). In 142 clinical specimens from patients with CRC, we also assessed the association of SIRT3 protein levels (high/low) and prognosis.

RESULTS:

SIRT3 expression correlated with mtROS generation and apoptosis induction in cells treated with anticancer agents. Suppressing SIRT3 increased mtROS levels and cell sensitivity to anticancer agents. SIRT3 knockdown decreased SOD2 expression and activity, and suppressing SOD2 also improved sensitivity to anticancer drugs. In addition, SIRT3 was recruited with PGC-1α under oxidative stress, and suppressing SIRT3 decreased PGC-1α expression and mitochondrial function. PGC-1α knockdown decreased mitochondrial activity and increased apoptosis in cells treated with anticancer drugs. In resected CRC specimens, high vs low SIRT3 protein levels were associated with significantly reduced cancer-specific survival.

CONCLUSIONS:

SIRT3 expression affected CRC cell chemoresistance through SOD2 and PGC-1α regulation and was an independent prognostic factor in CRC. SIRT3 may be a novel target for CRC therapies and a predictive marker of sensitivity to chemotherapy.

• Authors: Masakatsu Paku, Naotsugu Haraguchi, Mitsunobu Takeda, Shiki Fujino, Takayuki Ogino, Hidekazu Takahashi, Norikatsu Miyoshi, Mamoru Uemura, Tunekazu Mizushima, Hirofumi Yamamoto, Yuichiro Doki, Hidetoshi Eguchi
• Journal: Annals of surgical oncology (Ann Surg Oncol) Vol. 28 Issue 8 Pg. 4720-4732 (Aug 2021) ISSN: 1534-4681 [Electronic] United States
• PMID: 33393034 (Publication Type: Journal Article)

Chemical References

• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Reactive Oxygen Species
• Superoxide Dismutase
• SIRT3 protein, human
• Sirtuin 3

Topics

• Colorectal Neoplasms (drug therapy, genetics, metabolism)
• Drug Resistance, Neoplasm
• Humans
• Mitochondria (metabolism)
• Oxidative Stress
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Reactive Oxygen Species (metabolism)
• Sirtuin 3 (genetics, metabolism)
• Superoxide Dismutase (genetics, metabolism)