Inhibitors of atypical protein kinase C and their use in treating hedgehog pathway-dependent cancers
Methods and compositions are provided for modulating Hedgehog (Hh) pathway signaling in a cell. Aspects of the methods include methods for inhibiting Hh pathway-promoted cancer proliferation and/or metastasis that is promoted by Hh pathway signaling, methods for treating cancers promoted by Hh pathway signaling, and methods for screening candidate agents for the ability to treat a cancer promoted by Hh pathway signaling. In addition, reagents and kits thereof that find use in practicing the subject methods are provided.
1. A method of inhibiting Hedgehog (Hh) pathway-promoted cancer cell proliferation, comprising:
determining Gli activity in a cancer cell to identify the cancer cell as a Hh-induced cancer cell, wherein Gli activity is increased in the Hh-induced cancer cell and aPKC iota activates Gli;
contacting the Hh-induced cancer cell with an aPKC iota antagonist in an amount effective to inhibit Hh pathway-induced proliferation of the cell,
wherein the aPKC iota antagonist consists essentially of SEQ ID NO:4.
2. The method according to claim 1 , wherein the cell is in vivo.
3. The method according to claim 1 , wherein the cell is in vitro.
4. The method according to claim 1 , wherein the cell comprises a constitutively active Hh pathway.
5. The method according to claim 1 , wherein aPKC iota antagonist consists of SEQ ID NO: 4.
6. The method of claim 1 , wherein determining Gli activity comprises measuring amount of phosphorylated Gli.
7. The method of claim 1 , wherein determining Gli activity comprises measuring the amount of binding of Gli to a target DNA sequence comprising a sequence to which phosphorylated Gli binds.
8. A method of inhibiting Hedgehog (Hh) pathway-promoted Basal cell carcinoma (BCC) proliferation, comprising:
determining Gli activity in the BCC to identify the BCC as a Hh-induced BCC, wherein Gli activity is increased in the Hh-induced BCC and wherein aPKC iota activates Gli; and
contacting the BCC with an aPKC iota antagonist in an amount effective to inhibit Hh pathway-induced proliferation of the cell,
wherein the aPKC iota antagonist consists essentially of SEQ ID NO:4.
9. The method according to claim 8 , wherein the BCC comprises a constitutively active Hh pathway.
10. The method according to claim 8 , wherein the contacting comprises administering the aPKC iota antagonist topically.
11. The method according to claim 8 , wherein aPKC iota antagonist consists of SEQ ID NO: 4.
12. A method of inhibiting Hedgehog (Hh) pathway-promoted cancer cell proliferation, comprising:
determining Gli activity in a cancer cell to identify the cancer cell as a Hh-induced cancer cell and determining aPKCiota activity in the cancer cell, wherein Gli activity and aPKCiota is increased in the Hh-induced cancer cell and aPKC iota activates Gli; and
contacting the cancer cell with an aPKC iota antagonist in an amount effective to inhibit Hh pathway-induced proliferation of the cell,
wherein the aPKC iota antagonist consists essentially of SEQ ID NO:4.
13. The method according to claim 12 , wherein the cancer cell comprises a constitutively active Hh pathway.
14. The method according to claim 12 , wherein the contacting comprises administering the aPKC iota antagonist topically.
15. The method according to claim 12 , wherein aPKC iota antagonist consists of SEQ ID NO: 4.