Clofazimine Treatment Modulates Key Non-Coding RNAs Associated with Tumor Progression and Drug Resistance in Lethal...

Area of Science:

• Oncology
• Pharmacology
• Cancer Biology

Background:

• Metastatic castration-resistant prostate cancer (mCRPC) presents significant clinical challenges, including increased aggressiveness and resistance to standard therapies like taxanes.
• Cancer stem cells (CSCs) and epithelial-to-mesenchymal transition (EMT) contribute to mCRPC progression and treatment resistance.
• Clofazimine (CLF), an FDA-approved drug for leprosy, has demonstrated efficacy in other hematologic malignancies.

Purpose of the Study:

• To evaluate the efficacy of Clofazimine (CLF) as a single agent and in combination with taxanes for treating diverse mCRPC patient cell lines.
• To investigate the impact of CLF on prostate cancer cell migration, stemness (ALDH activity), and epithelial-to-mesenchymal transition (EMT).
• To elucidate the molecular mechanisms underlying CLF's anti-cancer effects in mCRPC.

Main Methods:

• Utilized a panel of mCRPC cell lines representing patient diversity.
• Employed microfluidic assays to assess cancer cell migration and metastatic potential.
• Measured aldehyde dehydrogenase (ALDH) activity as a marker for cancer stem cells (CSCs).
• Performed bulk and single-cell RNA sequencing (RNAseq), functional validation, and in silico analysis.

Main Results:

• CLF demonstrated efficacy as a single agent and in combination with taxanes against mCRPC cell lines.
• CLF significantly reduced cancer cell migration and metastatic potential.
• CLF decreased ALDH activity, indicating a reduction in cancer stem-like cells (CSCs).
• RNAseq analysis revealed that CLF induces apoptosis, ER stress, and mitochondrial dysfunction, while modulating non-coding RNAs like MALAT1 and NEAT1.

Conclusions:

• Clofazimine (CLF) is a potent therapeutic agent against metastatic castration-resistant prostate cancer (mCRPC), both alone and in combination with taxanes.
• CLF targets key drivers of mCRPC progression, including cancer cell migration, stemness, and EMT.
• The molecular mechanisms involve apoptosis induction, ER stress, mitochondrial dysfunction, and modulation of critical non-coding RNAs, highlighting CLF's potential in overcoming drug resistance.