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<p>Clear-cell renal cell carcinoma (ccRCC) is characterized by VHL-associated metabolic reprogramming, including enhanced glycolysis and lipid biosynthesis, which may create therapeutic vulnerabilities. However, mTOR inhibitors such as temsirolimus often show limited efficacy due to adaptive metabolic compensation. We investigated whether simvastatin-induced metabolic stress enhances sensitivity to mTOR inhibition in a context-dependent manner in ccRCC. VHL-mutant (A498) and VHL-wild-type (Caki1) ccRCC cells were treated with simvastatin and temsirolimus, alone or in combination. Cell viability, colony formation, migration, Seahorse metabolic flux analysis, and Western blotting were performed. Mechanistic studies included shRNA-mediated knockdown of <i>LKB1</i>/<i>AMPKα1/α2</i> and pharmacological modulation using Compound C and AICAR. Antitumor efficacy was evaluated in a Caki1 subcutaneous xenograft model in nude mice. Temsirolimus induced modest growth inhibition, whereas simvastatin produced stronger dose- and time-dependent effects. Combination treatment (simvastatin 2.5&#xa0;µM + temsirolimus 100&#xa0;nM) further reduced cell viability. Interaction analysis revealed a cell-dependent response, with synergism in A498 cells (combination index (CI), 0.31–0.77) and antagonistic-to-additive effects in Caki1 cells (CI, 1.6–2.7). Mechanistically, simvastatin activated LKB1–AMPK signaling, suppressed AKT/mTOR activity, reduced glycolysis (↓pPFKFB2), increased FBP1 expression, and downregulated lipid biosynthesis enzymes (FASN, SCD), thereby promoting ER stress and apoptosis. In vivo, combination therapy significantly suppressed tumor growth compared with monotherapy and alleviated temsirolimus-induced hypercholesterolemia without apparent toxicity. Simvastatin-induced metabolic perturbation enhances mTOR inhibition in a cell-dependent manner, supporting dual metabolic targeting as a potential therapeutic strategy in ccRCC.</p> Graphical Abstract <p>Simvastatin activates the LKB1–AMPK pathway to inhibit AKT/mTOR signaling, glycolysis, and lipid synthesis in clear-cell renal cell carcinoma (ccRCC). This metabolic stress triggers ER stress-mediated autophagy and apoptosis, thereby sensitizing ccRCC cells to temsirolimus and enhancing tumor suppression in vivo.</p> <p></p>

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Simvastatin enhances the antitumor activity of temsirolimus through AMPK-associated metabolic modulation in clear-cell renal cell carcinoma

  • 期刊论文

  • 发表日期：

    2026年7月24日

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  • Hsuan-Yu Chen,
  • Chien-Jui Cheng,
  • Te-Hsing Hsu,
  • Szu-Yu Tung,
  • Fang-Ning Chou,
  • Mantosh Kumar Satapathy,
  • Shu-Hui Juan

摘要

Clear-cell renal cell carcinoma (ccRCC) is characterized by VHL-associated metabolic reprogramming, including enhanced glycolysis and lipid biosynthesis, which may create therapeutic vulnerabilities. However, mTOR inhibitors such as temsirolimus often show limited efficacy due to adaptive metabolic compensation. We investigated whether simvastatin-induced metabolic stress enhances sensitivity to mTOR inhibition in a context-dependent manner in ccRCC. VHL-mutant (A498) and VHL-wild-type (Caki1) ccRCC cells were treated with simvastatin and temsirolimus, alone or in combination. Cell viability, colony formation, migration, Seahorse metabolic flux analysis, and Western blotting were performed. Mechanistic studies included shRNA-mediated knockdown of LKB1/AMPKα1/α2 and pharmacological modulation using Compound C and AICAR. Antitumor efficacy was evaluated in a Caki1 subcutaneous xenograft model in nude mice. Temsirolimus induced modest growth inhibition, whereas simvastatin produced stronger dose- and time-dependent effects. Combination treatment (simvastatin 2.5 µM + temsirolimus 100 nM) further reduced cell viability. Interaction analysis revealed a cell-dependent response, with synergism in A498 cells (combination index (CI), 0.31–0.77) and antagonistic-to-additive effects in Caki1 cells (CI, 1.6–2.7). Mechanistically, simvastatin activated LKB1–AMPK signaling, suppressed AKT/mTOR activity, reduced glycolysis (↓pPFKFB2), increased FBP1 expression, and downregulated lipid biosynthesis enzymes (FASN, SCD), thereby promoting ER stress and apoptosis. In vivo, combination therapy significantly suppressed tumor growth compared with monotherapy and alleviated temsirolimus-induced hypercholesterolemia without apparent toxicity. Simvastatin-induced metabolic perturbation enhances mTOR inhibition in a cell-dependent manner, supporting dual metabolic targeting as a potential therapeutic strategy in ccRCC.

Graphical Abstract

Simvastatin activates the LKB1–AMPK pathway to inhibit AKT/mTOR signaling, glycolysis, and lipid synthesis in clear-cell renal cell carcinoma (ccRCC). This metabolic stress triggers ER stress-mediated autophagy and apoptosis, thereby sensitizing ccRCC cells to temsirolimus and enhancing tumor suppression in vivo.