CoA Synthase (COASY) Mediates Radiation Resistance via PI3K Signaling in Rectal Cancer

Abstract

Neoadjuvant radiation is standard of care for locally advanced rectal cancer. Response to radiation is highly variable and directly linked with survival. However, there currently are no validated biomarkers or molecular targets to predict or improve radiation response, which would help develop personalized treatment and ideally targeted therapies. Here, we identified a novel biomarker, coenzyme A synthase (COASY), whose mRNA expression was consistently elevated in radioresistant human rectal cancers. This observation was validated in independent patient cohorts and further confirmed in colorectal cancer cell lines. Importantly, genetic overexpression and knockdown yielded radioresistant and sensitive phenotypes, respectively, in vitro and in vivo. COASY-knockdown xenografts were more vulnerable to radiation, showing delayed tumor growth, decreased proliferation, and increased apoptosis.Mechanistically, COASY protein directly interacted with the PI3K regulatory subunit PI3K-P85a, which increased AKT and mTOR phosphorylation, enhancing cell survival. Furthermore, shRNA COASY knockdown disrupted downstream PI3K pathway activation and also hindered DNA double-strand break repair, which both led to improved radiosensitivity. Collectively, this work reveals for the first time the biological relevance of COASY as a predictive rectal cancer biomarker for radiation response and offers mechanistic evidence to support COASY as a potential therapeutic target.Significance: COASY is a novel radiotherapy response modulator in rectal cancer that regulates PI3K activation and DNA repair. Furthermore, COASY levels directly correlate with radiation response and serve as a predictive biomarker.

Effects of the Novel PFKFB3 Inhibitor KAN0438757 on Colorectal Cancer Cells and Its Systemic Toxicity Evaluation In Vivo

“…Tissue collection and gene expression profiling have been already described for the rectal cancer cohort [ 72 , 73 , 74 ]. Briefly, tissue samples were obtained from patients with locally advanced rectal cancer patients.…”

The Pathophysiological Role of CoA

“…In vitro and in vivo studies proved that increased levels of COASY were directly related to radiation resistance, possible by enhancing DNA repair efficiency and/or by activation of the PI3K/AKT/mTOR pathway. Knocking down COASY resulted in a better radiation response, including delayed tumor growth, inhibited cell proliferation, and increased activation of apoptosis after irradiation [122,123]. It would be interesting to know whether heterogeneity in response to radiation alterations in COASY expression levels is characteristic of other types of cancers.…”

Identifying new targets for rectal cancer treatment

“…Identifying reasons for this heterogeneity in response, and discovering novel targets to improve radiation sensitivity will lead to treatment advances. We have recently discovered Coenzyme A synthase (COASY) as a novel protein that serves both as a predictive marker for, and has a critical function in radiation resistance [ 4 ].…”

“…Mechanistically, we demonstrated a direct interaction between COASY protein and the PI3K regulatory subunit PI3K-P85α, which increased AKT and mTOR phosphorylation, enhancing cell survival after irradiation. Additionally, shRNA COASY -knockdown increased DNA double-strand breaks after irradiation [ 4 ].…”

“…Our findings may have broader implications beyond rectal cancer as the level of COASY was found to be significantly overexpressed in tumors compared to normal tissues in several other cancers [ 4 ]. Furthermore, the ubiquitous role of PI3K/Akt signaling in cancer suggests that our results may be relevant to several cancer types.…”