Cavin-1 is essential for the tumor-promoting effect of caveolin-1 and enhances its prognostic potency in pancreatic cancer

Nucleoside analogues are the most promising drugs for the treatment of pancreatic cancer to date. However, their use is often limited due to toxic side effects. Aptamer-mediated targeted delivery of these drugs to cancer cells could maximize their effectiveness and concomitantly minimize the toxic side effects by reducing uptake into normal cells. Previously, we identified a pancreatic cancer-specific, nuclease-resistant RNA aptamer, SQ2, which binds to alkaline phosphatase placental-like 2 (ALPPL2), a putative biomarker for pancreatic cancer. In this study, we demonstrate that the aptamer can be internalized into pancreatic cancer cells and can thus be used for the targeted delivery of therapeutics. Using the aptamer as a ligand, we established that glycophosphatidylinositol-anchored ALPPL2 is internalized by the cells through clathrin-independent and caveolae-dependent or dynamin-mediated cell-type-dependent pathways. Finally, we show that SQ2 can deliver nucleoside drug 5-fluoro-2'-deoxyuridine specifically to ALPPL2-expressing pancreatic cancer cells, inhibiting cell proliferation.

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“…in Capan-1 cells [28,29]. This suggests the presence of alternative caveolin-independent pathways, as seen earlier in caveolae-null mice [30].…”

Section: Alppl2-mediated Clathrin-independent Pathways Are Involved Isupporting

confidence: 67%

ALPPL2 Aptamer-Mediated Targeted Delivery of 5-Fluoro-2′-Deoxyuridine to Pancreatic Cancer

Dua

Sajeesh

Kim

et al. 2015

Nucleic Acid Therapeutics

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“…In this context, Cavin1 was shown to modulate the oncogenic function of Cav1 and to cooperate with Cav1 to enhance aggressiveness. [133] The role of Cavin1 in cancer is in agreement with the co-transcriptional regulation of Cavin1 and Cav1.…”

Section: Caveolae New Partners and Cancermentioning

confidence: 63%

Caveolae and cancer: A new mechanical perspective

Lamaze¹,

Torrino²

2015

Biomed J

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“…For example, Cavin-1 was reported to decrease the malignant behavior of prostate PC3 cancer cells through different mechanisms, [89][90][91][92][93] although being essential for the tumor-promoting effect of Cav-1 in pancreatic cancer 94 and for multidrug resistance in breast cancer lines. 95 By analogy, even the role of Cav-1 in cancer appears to be ambiguous, because Cav-1 may behave as either a tumor suppressor or oncopromoter depending on the type of tumor.…”

Section: Discussionmentioning

confidence: 99%

Cavin-1 and Caveolin-1 are both required to support cell proliferation, migration and anchorage-independent cell growth in rhabdomyosarcoma

Faggi

Chiarelli

Colombi

et al. 2015

Laboratory Investigation

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Rhabdomyosarcoma (RMS) is a childhood soft tissue tumor with broad expression of markers that are typically found in skeletal muscle. Cavin-1 is a recently discovered protein actively cooperating with Caveolin-1 (Cav-1) in the morphogenesis of caveolae and whose role in cancer is drawing increasing attention. Using a combined in silico and in vitro analysis here we show that Cavin-1 is expressed in myogenic RMS tumors as well as in human and primary mouse RMS cultures, exhibiting a broad subcellular localization, ranging from nuclei and cytosol to plasma membrane. In particular, the coexpression and plasma membrane interaction between Cavin-1 and Cav-1 characterized the proliferation of human and mouse RMS cell cultures, while a downregulation of their expression levels was observed during the myogenic differentiation. Knockdown of Cavin-1 or Cav-1 in the human RD and RH30 cells led to impairment of cell proliferation and migration. Moreover, loss of Cavin-1 in RD cells impaired the anchorage-independent cell growth in soft agar. While the loss of Cavin-1 did not affect the Cav-1 protein levels in RMS cells, Cav-1 overexpression and knockdown triggered a rise or depletion of Cavin-1 protein levels in RD cells, respectively, in turn reflecting on increased or decreased cell proliferation, migration and anchorage-independent cell growth. Collectively, these data indicate that the interaction between Cavin-1 and Cav-1 underlies the cell growth and migration in myogenic tumors. Rhabdomyosarcoma (RMS) is a childhood soft tissue sarcoma exhibiting broad expression of skeletal muscle markers, 1-3 such as Pax7, MyoD, Myogenin, desmin and muscle-specific actin. 4,5 Cells of origin in RMS may be different muscular and non-muscular cell precursors, 6-8 such as muscle satellite cells (SCs), 9-11 and myoblasts 9,10,12-14 or adipocytes, 15 which are responsible of two major histological subtypes known as embryonal (ERMS) and alveolar (ARMS). The most common ERMS variant arises in children usually o5 years on distinct body sites, such as head, neck and genitourinary regions, while ARMS typically arises in the muscular limb extremities of adolescents and is characterized by poorer prognosis. 16 The genomic landscape causative of ERMS is characterized by a number of genetic lesions and/or somatic mutations that deliberately sustain the activity of different receptors, such as IGF1R, FGFR4 and Patched, 17-21 and related downstream pathways (i.e., RAS/ERK, PI3K/AKT and Sonic Hedgehog signaling). 11,22 In addition, defects in tumor suppressors (i.e., p53), 23 cell cycle regulatory genes (i.e., N-Myc, Rb1) 21,24 and structural proteins involved in muscular integrity (i.e., dystrophin, alpha-sarcoglycan and dysferlin) have been reported. [25][26][27][28][29][30] Conversely, ARMS is dominated by the presence of specific chromosomal translocations leading to expression of the fused Pax3-Foxo1 and Pax7-Foxo1 factors, that driving in a cell cycle manner the transcription of several genes normally restricted to the embryonal development f...

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Cavin-1 is essential for the tumor-promoting effect of caveolin-1 and enhances its prognostic potency in pancreatic cancer

Cited by 59 publications

References 35 publications

ALPPL2 Aptamer-Mediated Targeted Delivery of 5-Fluoro-2′-Deoxyuridine to Pancreatic Cancer

ALPPL2 Aptamer-Mediated Targeted Delivery of 5-Fluoro-2′-Deoxyuridine to Pancreatic Cancer

Caveolae and cancer: A new mechanical perspective

Cavin-1 and Caveolin-1 are both required to support cell proliferation, migration and anchorage-independent cell growth in rhabdomyosarcoma

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