CD44+ cells determine fenofibrate-induced microevolution of drug-resistance in prostate cancer cell populations

Abstract

Combinations of metabolic blockers (including fenofibrate) with chemotherapeutic drugs interfere with the drug-resistance of prostate cancer cells. However, their effect on cancer stem cells-dependent microevolution of prostate cancer malignancy remains unaddressed. Here, we hypothesize that the combined docetaxel/fenofibrate treatment prompts the selective expansion of cancer stem cells that affects the microevolution of their progenies. Accordingly, we adapted a combined in vitro/in vivo approach to identify biological and therapeutic consequences of this process. Minute subpopulations of docetaxel-resistant CD133high and/or CD44high cancer stem cell-like (SCL) cells were found in prostate cancer DU145 and PC3 cell populations. When pretreated with docetaxel, they readily differentiated into docetaxel-resistant CD44negative “bulk” cells, thus accounting for the microevolution of drug-resistant cell lineages. Combined docetaxel/fenofibrate treatment induced the generation of poly(morpho)nuclear giant cells and drug-resistant CD44high SCL cells. However, the CD44negative offspring of docetaxel- and docetaxel/fenofibrate-treated SCLs remained relatively sensitive to the combined treatment, while retaining enhanced resistance to docetaxel. Long-term propagation of drug-resistant SCL-derived lineages in the absence of docetaxel/fenofibrate resulted in their reverse microevolution toward the drug-sensitivity and invasive phenotype. Consequently, prostate tumors were able to recover from the combined docetaxel/fenofibrate stress after the initial arrest of their expansion in vivo. In conclusion, we have confirmed the potential of fenofibrate for the metronomic treatment of drug-resistant prostate tumors. However, docetaxel/fenofibrate-induced selective expansion of hyper-resistant CD44high SCL prostate cells and their “bulk” progenies prompts the microevolution of prostate tumor drug-resistance. This process can limit the implementation of metabolic chemotherapy in prostate cancer treatment.

Acquired drug resistance interferes with the susceptibility of prostate cancer cells to metabolic stress

“…We did not reveal GJIC involvement in the adaptation of PC-3_DCX20 cells to DCX/MET-induced stress (not shown). Neither did DCX/FF-treatment upregulate Cx43 in these cells (not shown), even though it has previously been shown to trigger an expansion of super-resistant and invasive prostate cancer cell lineages from CD44 + cells [28]. Our data indicate that Cx43 can cooperate with Snail-1 via the (hemi)channel-(in)dependent control of mitochondrial stress [36,47,48] and cell invasiveness [33,[49][50][51].…”

“…We have previously shown that fenofibrate increases the sensitivity of drug-resistant prostate cancer cell lineages to chemotherapeutics [14]. Concomitantly, we observed an array of self-defense responses of prostate cancer cells that survive the initial chemotherapeutic/metabolic shock [28]. Similarly, metformin was shown to interfere with the acquired drug resistance of prostate cancer cells [17].…”

Understanding and targeting prostate cancer cell heterogeneity and plasticity

“…A Pubmed search with ‘Prostate Cancer Stem Cells’ as the Keyword would turn up > 3000 references. These reported PCSCs manifest a wide diversity of phenotypes including, among others, ABCG2 + [ 218 ], CD133 + [ 219 , 220 , 236 ], CD133 + α2β1 + [ 219 ], CD44 + [ 219 , 232 , 299 , 311 ], ALDH +/hi [ 224 ], MHC −/lo (and PSA −/lo ) [ 226 ], LP-like [ 227 , 238 ] or basal-like [ 231 ], Trop2 +/hi [ 230 ], TOP2A-[ 243 ], hTERT hi [ 250 ], Bmi1 + Sox2 + [ 260 ], CD24 +/hi [ 261 ], CXCR2 + [ 272 ], Zeb1 + [ 280 ], holoclone-forming cells [ 291 ], and CD117(KIT) + [ 310 ]. Many of these PCSC phenotypes overlap with the PCSCs reported by our lab.…”

“…PCSCs, in spite of phenotypic diversity, are commonly endowed with high clonogenic and tumor-initiating/tumor-propagating activities. Importantly, PCSCs have been reported to be intrinsically therapy-resistant, including resistance to castration, chemotherapy, radiotherapy and, likely, immunotherapy [ 2 , 3 , 125 , 131 , 138 , 218 , 226 , 227 , 251 – 253 , 265 , 278 , 299 , 300 , 310 , 313 , 315 ]. For example, the PSA −/lo PCa cells are resistant to castration, antiandrogens, prooxidants and chemodrugs [ 131 , 144 ] and ABCG2 + PCSCs are resistant to ARSIs due to increased efflux of androgens [ 218 ].…”

“…For example, the PSA −/lo PCa cells are resistant to castration, antiandrogens, prooxidants and chemodrugs [ 131 , 144 ] and ABCG2 + PCSCs are resistant to ARSIs due to increased efflux of androgens [ 218 ]. Similarly, the PSA −/lo /MHC −-/l o PCSCs are resistant to docetaxel as a result of enhanced Notch and Hedgehog signaling [ 226 ], and the CD4 4 + [ 299 ], LP-like [ 227 , 252 ] and hypoxia-induced [ 265 ] PCSCs are all inherently castration- and chemo-resistant. Finally, sphere-derived PCSCs are resistant toγ?d T cell-mediated cytotoxicity [ 300 ] and PCSCs, like many other CSCs, are generally ‘immuno-deficient’ lacking the expression of many immunogenic molecules [ 160 ].…”