Lipid Catabolism via CPT1 as a Therapeutic Target for Prostate Cancer

Abstract

Prostate cancer (PCa) is the most commonly diagnosed malignancy among western men and accounts for the second leading cause of cancer-related deaths. PCa tends to grow slowly and recent studies suggest that it relies on lipid fuel more than on aerobic glycolysis. However, the biochemical mechanisms governing the relationships between lipid synthesis, lipid utilization, and cancer growth remain unknown. To address the role of lipid metabolism in PCa we have used Etomoxir and Orlistat, clinically safe drugs that block lipid oxidation and lipid synthesis/lipolysis, respectively. Etomoxir is an irreversible inhibitor of the carnitine palmitoyltransferase (CPT1) enzyme that decreases beta oxidation in the mitochondria. Combinatorial treatments using Etomoxir and Orlistat resulted in synergistic decreased viability in LNCaP, VCaP and patient-derived benign and PCa cells. These effects were associated with decreased androgen receptor (AR) expression, decreased mammalian target of Rapamycin (mTOR) signaling and increased caspase-3 activation. Knockdown of CPT1A enzyme in LNCaP cells resulted in decreased palmitate oxidation but increased sensitivity to Etomoxir, with inactivation of AKT kinase and activation of caspase-3. Systemic treatment with Etomoxir in nude nice resulted in decreased xenograft growth over 21 days, underscoring the therapeutic potential of blocking lipid catabolism to decrease PCa tumor growth.

Organ-Specific Cancer Metabolism and Its Potential for Therapy

“…Moreover, the short chain fatty acids, which then are released from the peroxisome might further fuel the TCA cycle by their full β-oxidation in the mitochondria. Although enzymes of mitochondrial β-oxidation are not increased in prostate cancer [140], it has been shown that etomoxir-mediated inhibition of mitochondrial β-oxidation at the level of carnitine palmitoyltransferase 1 induces cell death in prostate cancer cell lines [143]. Interestingly, prostate cancer also induces fatty acid biosynthesis by overexpressing fatty acid synthase early during tumor progression without lipid accumulation [144,145], which is further consistent with 11 C-acetate PET/CT experiments [146].…”

“…Moreover, inhibition of fatty acid biosynthesis and oxidation was reported to inhibit tumor growth [143,148,149]. Yet, cancer cell lines, such as DU-145, LNCaP and PC-3 exhibit an elevated fatty acid uptake from the environment, which renders them less sensitive to inhibition of fatty acid biosynthesis [150][151][152].…”

Metabolic Plasticity as a Determinant of Tumor Growth and Metastasis

“…During transformation to early lesions, prostate cancer cells progressively switch toward OXPHOS-dependent metabolism (47). Interestingly, prostate cancer cells prioritize glycolytic metabolism during late stages of cancer progression, rendering them sensitive to 2-DG (13,(48)(49)(50)(51)(52)(53)(54). Thus, prostate cancer cells exhibit a mixed phenotype, where both glycolysis and OXPHOS are required for energy metabolism at different stage of disease progression (Table 1; ref.…”

The Role of PGC1α in Cancer Metabolism and its Therapeutic Implications

“…FAO is activated in several type of cancers, and the transcription factor, PPARa, is the main regulator of this process (80)(81)(82)(83). PPARa can be activated by endogenous fatty acid, fatty acid derivatives or fibrates, and is coregulated by PGC1a (84,85).…”