Rapalogs can promote cancer cell stemness in vitro in a Galectin-1 and H-ras-dependent manner

Abstract

Currently several combination treatments of mTor- and Ras-pathway inhibitors are being tested in cancer therapy. While multiple feedback loops render these central signaling pathways robust, they complicate drug targeting.Here, we describe a novel H-ras specific feedback, which leads to an inadvertent rapalog induced activation of tumorigenicity in Ras transformed cells. We find that rapalogs specifically increase nanoscale clustering (nanoclustering) of oncogenic H-ras but not K-ras on the plasma membrane. This increases H-ras signaling output, promotes mammosphere numbers in a H-ras-dependent manner and tumor growth in ovo. Surprisingly, also other FKBP12 binders, but not mTor-inhibitors, robustly decrease FKBP12 levels after prolonged (>2 days) exposure. This leads to an upregulation of the nanocluster scaffold galectin-1 (Gal-1), which is responsible for the rapamycin-induced increase in H-ras nanoclustering and signaling output. We provide evidence that Gal-1 promotes stemness features in tumorigenic cells. Therefore, it may be necessary to block inadvertent induction of stemness traits in H-ras transformed cells by specific Gal-1 inhibitors that abrogate its effect on H-ras nanocluster. On a more general level, our findings may add an important mechanistic explanation to the pleiotropic physiological effects that are observed with rapalogs.

Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy

“…In the latter study, FKBPL overexpression in breast cancer cells was shown to reduce the number of CSCs via downregulation of DLL4 and Notch4 [179]. In turn, FKBP12 knockdown in breast cancer cell enhanced the mammosphere formation and other stemness features, whereas FKBP12 overexpression exerted the opposite effects [181].…”

“…The other member of the immunophilin family, FKBP51, was shown to be associated with the invasiveness and metastatic potential of melanoma SCs [190,191] and with the enhanced cell migration and invasion in papillary thyroid carcinomas [192], and also with cancer stemness, tumor recurrence, and poor prognosis in oral squamous cell carcinomas [183]. A contribution of FKBP4 to cancer stemness manifestations, such as self-renewal, spheroid formation, and chemoresistance, has been reported as well [181,182]. Meanwhile, a pivotal role of cyclophilin A in maintaining stemness in gliomas has been established: By means of direct binding to β-catenin, cyclophilin A regulates the interactions of β-catenin with Wnt target gene promoters and TCF4, thus resulting in an enhancement of transcriptional activity [198].…”

“…There are published data indicating a link between peptidyl-prolyl isomerases and cancer stemness. It was shown that FKBP12 knockdown increased the mammosphere formation and tumorigenicity in breast cancer cell lines [181]. By means of proteomics-and microarray-based investigations, FKBP4 was identified as one of the upregulated (marker) proteins in neoplastic SCs from childhood germ cell tumors [182], mammosphere-derived breast CSCs [150], and oral squamous cell carcinomas [183].…”

“…Except FKBPL [178,179] and FKBP12 [181], peptidyl-prolyl isomerases are ones of the endogenous drivers of cancer stemness, which control different points in tumor cell regulation, including gene transcription, signaling networks, the mitochondrial permeability transition pore, and others. Consequently, the cancer stemness-related activities of peptidyl-prolyl isomerases can be suppressed by specific inhibitors or certain microRNAs.…”

Functional link between plasma membrane spatiotemporal dynamics, cancer biology, and dietary membrane-altering agents

“…It has been reported that cancer-associated mutations in HRas, KRas, and NRas oncoproteins increase their activity through augmented nanoclustering of Ras on membranes [22]. Similarly, Ras clustering modulation by the overexpression of various galectins (e.g., Galectin-1 and Galectin-3), which is observed in breast, pancreatic, colorectal, and other cancers, can increase Ras nanoclustering and its oncogenic output [24, 246, 248–251]. Likewise, nanoclustering of other plasma membrane components, i.e., carbohydrates and lipids, plays an important role in cancer.…”